KR20050108373A - Pyridinium salts, compounds and methods of use - Google Patents

Abstract

Compounds of pyridinium salts and methods of their use in medicine, particularly in the prophylaxis and treatment of inflammatory conditions, infectious conditions, as well as immune disorders are disclosed. The present invention also relates to methods of controlling fungi and/or bacteria. Additionally, the present invention relates to controlling fungal or bacterial infestations relating to industrial and agricultural uses. The present invention may also be used to control insects.

Description

Pyridinium salts, compounds and methods of use}

Cross Reference to Related Application

This application is directed to US Provisional Application No. 60 / 480,995, filed Jun. 23, 2003, US Provisional Application No. 60 / 524,775, filed November 25, 2003, US Provisional Application No. 60, filed November 25, 2003. / 525,075, US Provisional Application No. 60 / 524,784, filed November 25, 2003, and US Provisional Application No. 60 / 450,599, filed March 3, 2003, the disclosures of which are fully Incorporated herein by reference as is.

The present invention relates generally to compounds of pyridinium salts and methods of their medical use, in particular in the prevention and treatment of inflammatory, allergic and infectious symptoms as well as immune diseases. The invention also relates to a method for controlling fungi and / or bacteria. More specifically, the present invention relates to a method for controlling the infestations of fungi or bacteria associated with industrial and agricultural use. The invention can also be used to control insects.

The present invention relates to pyridinium derivatives, methods for their preparation, pharmaceutical preparations comprising them, and their medical uses, especially in the prevention and treatment of inflammatory and infectious symptoms as well as immune diseases.

Stillbazium iodide is a known insect repellent reported to be effective against roundworms, nematodes, and worms. U. S. Patent No. 3,075, 975 and U. S. Patent No. 3, 085, 935 disclose methods for eradicating the prevalence of parasitic nematodes in the intestinal tract.

The binding of circulating white blood cells to the vascular endothelium is a significant phenomenon in the pathogenesis of the inflammatory response. Inflammation, infection, and immune mediators can stimulate the binding process by increasing the binding of leukocytes or endothelial cells on the cell surface through activity, upregulation, or induction of various binding molecules.

Currently available anti-inflammatory agents have limited efficacy and often have side effects. Monoclonal antibodies used experimentally in anti-binding therapies have theoretical disadvantages for the treatment of chronic diseases. Thus, the discovery and development of small molecules that specifically block or inhibit the leukocyte and endothelial binding interactions is an attractive field of therapeutic intervention.

In addition, there is a need to treat fungi and / or bacteria with new compounds. Fungi include organisms such as slime molds, fungi, embers, rust fungi, fungi, filamentous fungi, stake mushrooms, horse mushrooms, truffles and yeasts. Fungi are classified as their own kingdom because they absorb nutrients in solution directly through their cell walls and reproduce through spores. Filamentous fungi are common triggers of allergies and a large group of fungi that infect crops, plants and food. Filamentous fungi can exist as small particles called “coliform spores” present in indoor and outdoor air. There are more than 100,000 species on Earth. Filamentous fungi can grow wherever there is a source of moisture. Common filaments are Cladosporium, Penicillium, Aspergillus, Alternaria, Fusarium, Neurospora, Stachybotyrs ) And Muco, but are not limited thereto.

Soil-derived and seed-derived fungal pathogens of plants are the cause of serious economic losses in agricultural and horticultural industries worldwide. The pathogen causes diseases such as seed rot, root / foot rot, seedling blight and wilting disease. The disease usually reduces the vitality and yield of the parent body, plants. Serious disease infections can kill the parent body of the entire plant community and cause a total loss of crop yield.

Solutions to recurring problems of plant pathogens have been studied for decades. As certain crops become richer and the land area allocated to agriculture increases, there is an inherent need to use more efficient and effective agricultural techniques. As a result of the growing demand for crop yields, farmers often compromise their cultivation techniques by transplanting crops to suboptimal land, or by increasing the frequency of transplanting crops to specific sites. In doing so, crop nutrients are depleted and certain crop pathogens, in particular soil-derived or seed-derived pathogens, become more prevalent. Therefore, maintaining the health and productivity of each crop is becoming increasingly difficult.

There is also a broad need for compounds that control microorganisms outside of agriculture. The need is to treat the fabric to prevent powder bottle and rot; Treating surfaces and substrates to obtain sterilization conditions for medical, industrial, food processing and household purposes; Decking or treatment of building timber; Preparation of inks and paints to prevent filamentous fungus growth and bacterial degradation; Prevention and treatment of human and animal diseases; And the almost infinite range of applications that occur in our daily lives.

There is a continuing need for new antimicrobials. Although many compounds useful for the treatment of Gram-positive and Gram-negative bacterial infections and other microbial infections are known, the widespread use of such compounds is resistant to microbial strains, ie, microbial strains resistant to a particular antibiotic or group of antibiotics. And previously effective chemical compositions are no longer useful. In addition, known antibiotics and chemical compositions may be effective only against certain microbial strains or have limited activity against gram positive or gram negative, aerobic or anaerobic microorganisms.

1A-1G show various compounds comprising methyl on the pyridine ring at the nitrogen position.

2A-2G show various compounds comprising trifluoroethyl bound on the pyridine ring at the nitrogen position.

3A-3F illustrate compounds comprising isobutyl on the pyridine ring at the nitrogen position.

4A-4G show various compounds with ethyl bound on the pyridine ring at the nitrogen position.

Summary of the Invention

The present invention relates to methods and compositions comprising stilettoes. One aspect of the invention is a composition comprising a compound of formula I or a solvate thereof in a substantially E, E configuration:

The amino moiety above may be present in the ortho, meta or para position. X ^- is an anion may be a salt, R _1, R _2, R _3, or R ₄ is from the group consisting of methyl, ethyl, C _{1 -10-alkyl} (linear or branched), and alkenes (linear or branched) Are independently selected or R ₁ and R ₂ or R ₃ and R ₄ together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring; R ₅ is methyl, ethyl, C _{1 -10-alkyl} (linear or branched), alkenes (linear or branched), alkynes, n- propyl, i- propyl, n- butyl, i- butyl, substituted and unsubstituted aryl Moieties and substituted and unsubstituted benzyl moieties. The substituted and unsubstituted aryl moieties and substituted and unsubstituted benzyl moieties include lower alkyl, aryl, benzyl, acyl, amido, amino, alkoxy, carboxy, carboxy esters, alcohols, nitros, trifluoroalkoxy, trifluoro Alkyl and halo include, but are not limited to. In addition, R ₅ may be an organometallic compound such as organotin, organosilicon, or organogermanium. R ₅ may also be (CH ₂ ) _n -MR ₆ , where n is a number from 1 to 6. M is an organometallic compound such as tin, silicon, or germanium, and R ₆ is selected from the group consisting of propyl, butyl, or any alkyl compound.

The present invention also relates to a method for controlling fungi and / or bacteria comprising administering any compound of the formula or a solvate thereof:

X in the above ^- is an anion, and salt, R _1, R _2, R _3, or R ₄ are independently selected from methyl, ethyl, linear or branched C _{1 -10} alkyl, and the group consisting of alkenyl, R ₁ And R ₂ or R ₃ and R ₄ together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring. R ₅ is methyl, ethyl, C _{1 -10} alkyl, linear or branched alkenes, alkynes, n- propyl, i- propyl, n- butyl, i- butyl, substituted and unsubstituted aryl moieties and substituted and unsubstituted benzyl Selected from the group consisting of moieties. In addition, R ₅ may be an organometallic compound such as organotin, organosilicon, or organogermanium. R ₅ may also be (CH ₂ ) _n —MR ₆ , where n is a number from 1 to 6, M is an organometallic compound such as tin, silicon, or germanium, and R ₆ is propyl, butyl, Or any alkyl compound. Compounds of the invention are more commonly known as stilettoes.

The present invention also relates to a method of controlling an insect comprising administering a composition comprising any compound of the above formula or a solvate thereof.

The present invention also relates to a method of treating inflammation, allergic symptoms, infections and immune diseases comprising administering a composition comprising any compound of the above formula or a solvate thereof. The present invention further relates to a method for controlling fungi and / or bacteria comprising administering a composition comprising any compound of the above formula or a solvate thereof.

The present invention also relates to microcapsule compositions stabilized against environmental degradation.

Detailed Description of the Invention

These and other aspects of the invention will be described in more detail with respect to other embodiments described herein below. The invention can be embodied in different forms and is not limited to the embodiments described herein. Rather, the present embodiments will be fully and completely provided by the present embodiments and will fully convey the scope of the invention to those skilled in the art.

The terminology used in the specification of the present invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the present invention. As used in the specification and claims of the present invention, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the content clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

All publications, patent applications, patents, and other references cited herein are incorporated by reference in their entirety for the teachings relating to the sentences and / or paragraphs in which such documents exist.

The present invention relates to pyridinium derivatives, methods for their preparation, methods for their use and compositions comprising the derivatives. Stilbad Iodide is a known insect repellent reported to be effective against roundworms, nematodes, and worms. U.S. Patent No. 3,075,975 and U.S. Patent No. 3,085,935 disclose methods for eradicating the prevalence of parasitic nematodes in the intestinal tract. The compounds can be used to control fungi and / or bacteria for industrial use.

One embodiment of the invention includes a compound or a solvate thereof comprising the formula:

X in the above ^- is an anion, and salt, R _1, R _2, R _3, or R ₄ is the group consisting of methyl, ethyl, C _{1 -10-alkyl} (linear or branched), and alkenes (linear or branched) Or R ₁ and R ₂ or R ₃ and R ₄ together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring. X ⁻ is fluoride, chloride, bromide, iodide halide, mesylate, tosylate, naphthylate, nosylate, para-aminobenzoate, benzenesulfonate, besylate, lauryl sulfate, 2,4-diha Idahydroxy benzophenone, 2- (2-hydroxy-5'-methylphenyl) benzotriazole, ethyl 2-cyano-3,3-diphenyl acrylate and 5-butyl phenyl salicylate Can be. R ₅ is methyl, ethyl, C _{1 -10-alkyl} (linear or branched), alkenes (linear or branched), alkynes, n- propyl, i- propyl, n- butyl, i- butyl, substituted and unsubstituted aryl Moieties and substituted and unsubstituted benzyl moieties. In addition, R ₅ may be an organometallic compound such as organotin, organosilicon, or organogermanium. R ₅ may also be (CH ₂ ) _n —MR ₆ , where n is a number from 1 to 6, M is an organometallic compound such as tin, silicon, or germanium, and R ₆ is propyl, butyl, Or any alkyl compound.

Another embodiment of the invention includes a compound comprising the formula II or a solvate thereof:

X in the above ^- is an anion, and salt, R _1, R _2, R _3, or R ₄ is the group consisting of methyl, ethyl, C _{1 -10-alkyl} (linear or branched), and alkenes (linear or branched) Or R ₁ and R ₂ or R ₃ and R ₄ together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring. R ₅ is methyl, ethyl, C _{1 -10-alkyl} (linear or branched), alkenes (linear or branched), alkynes, n- propyl, i- propyl, n- butyl, i- butyl, substituted and unsubstituted aryl Moieties and substituted and unsubstituted benzyl moieties. X ⁻ is fluoride, chloride, bromide, iodide halide, mesylate, tosylate, naphthylate, nosylate, para-aminobenzoate, benzenesulfonate, besylate, lauryl sulfate, 2,4-diha Idaoxy benzophenone, 2- (2-hydroxy-5'-methylphenyl) benzotriazole, benzenesulfonate, besylate, ethyl 2-cyano-3,3-diphenyl acrylate and 5-butyl phenyl salicyl It can be selected from the group consisting of the rate. In addition, R ₅ may be an organometallic compound such as organotin, organosilicon, or organogermanium. R ₅ may also be (CH ₂ ) _n —MR ₆ , where n is a number from 1 to 6, M is an organometallic compound such as tin, silicon, or germanium, and R ₆ is propyl, butyl, Or any alkyl compound. The present invention is more commonly known as steel bars. One embodiment of formula I is 2,6-bis (p-pyrrolidinostyryl) pyridine methoxide.

In addition, the NR ₁ R ₂ and NR ₃ R ₄ moieties may be present at various positions as demonstrated by the following compounds.

Another embodiment includes Formula III, wherein the NR ₁ R ₂ moiety is at one meta position.

Formula IV depicts the NR ₁ R ₂ and NR ₃ R ₄ moieties both present at the meta position.

In the X ^- is the anion may be a salt, R _1, R _2, R _3, or R ₄ is composed of a methyl, ethyl, C _{1 -10-alkyl} (linear or branched), and alkenes (linear or branched) Or independently selected from the group, or R ₁ and R ₂ or R ₃ and R ₄ together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring. R ₅ is methyl, ethyl, C _{1 -10-alkyl} (linear or branched), alkenes (linear or branched), alkynes, n- propyl, i- propyl, n- butyl, i- butyl, substituted and unsubstituted aryl Moieties and substituted and unsubstituted benzyl moieties. R ₅ may also be (CH ₂ ) _n —MR ₆ , where n is a number from 1 to 6, M is an organometallic compound such as tin, silicon, or germanium, and R ₆ is propyl, butyl, Or any alkyl compound.

The compounds of the present invention may exist as geometric isomers. All such isomers, individually and as mixtures, are included within the scope of the invention for their industrial use. E, E isomers are one configuration of the invention and both cis and trans 2,6-positions of the E, E configuration are possible. In addition to the para and meta structures exemplified above, an ortho ortho orthogonal structure may be formed. The orthosorbent structure may comprise the same salts and moieties as disclosed above and throughout the application.

Some embodiments of the invention provide 1-ethyl- (E, -E) -2,6-bis [2- [4- (pyrrolidinyl) phenyl] ethenyl] pyridinium chloride, 1-ethyl- (E, -E) -2,6-bis [p- (l-pyrrolidinostyryl] pyridinium chloride, 1-methyl- (E, -E) -2,6-bis [2- [4- (pyrroli Diyl) phenyl] ethenyl] pyridinium chloride and 1-methyl- (E, -E) -2,6-bis [p- (1-pyrrolidinostyryl] pyridinium chloride.

In addition, the present invention may include a compound of formula V or a solvate thereof:

In the above, n is a number from 1 to 5, Z may be present at multiple positions on the phenyl ring and is selected from the group consisting of C, N, O, S and halogen, X ⁻ is an anionic salt, R ₁ , R _2, R _3, or R ₄ is not present (nothing), hydrogen, methyl, ethyl, C _{1 -10-alkyl} (linear or branched), alkenes (linear or branched), acetonitrile, benzene, pyridine, benzothiophene Independently selected from the group consisting of operes, trifluoroalkyl, difluoroalkyl, substituted and unsubstituted aryl moieties and substituted and unsubstituted benzyl moieties, or R ₁ and R ₂ or R ₃ and R ₄ are Together with the nitrogen atom to which they are attached, they form a pyrrolidino or piperidino ring. X ⁻ is fluoride, chloride, bromide, iodide halide, mesylate, tosylate, naphthylate, nosylate, para-aminobenzoate, benzenesulfonate, besylate, lauryl sulfate, 2,4-diha Idahydroxy benzophenone, 2- (2-hydroxy-5'-methylphenyl) benzotriazole, ethyl 2-cyano-3,3-diphenyl acrylate and 5-butyl phenyl salicylate Can be. R ₅ is methyl, ethyl, C _{1 -10-alkyl} (linear or branched), alkenes (linear or branched), alkynes, n- propyl, i- propyl, n- butyl, i- butyl, substituted and unsubstituted aryl Moieties and substituted and unsubstituted benzyl moieties. In addition, R ₅ may be an organometallic compound such as organotin, organosilicon, or organogermanium. R ₅ may also be (CH ₂ ) _n —MR ₆ , where n is a number from 1 to 6, M is an organometallic compound such as tin, silicon, or germanium, and R ₆ is propyl, butyl, Or any alkyl compound, provided that the compound is 1-ethyl- (Z, Z), (Z, E) or (E, Z) -2,6-bis [2- [4- (Pyrrolidinyl) phenyl] ethenyl] pyridinium chloride. 1-4 illustrate the combination of various compounds that may be formed in accordance with the present invention. The compounds may be of the E, E configuration and may be used for any of the uses disclosed herein.

The compounds according to the invention can be prepared according to any suitable method of organic chemistry. More specifically, compounds of formula (I) can be prepared by the methods disclosed in US Pat. No. 3,085,935, the disclosure of which is incorporated in its entirety.

In addition, embodiments of the present invention are formula VI

Two equivalents of aldehydes and quaternary ammonium salts of 2,6-lutidine

Included are compounds produced by synthesis, which include the preparation of compounds by condensation of.

The condensation reaction can be carried out in a lower alcohol with a catalyst such as a secondary amine (eg piperidine). When X ⁻ in the above formula is an iodide ion (corresponding to the alkyidoid salt of lutidine), the condensation product (formula I) is relatively insoluble and precipitates during the course of the reaction. The reaction yield of formula I can be calculated in almost positive amounts. Three times the amount of catalyst disclosed in US Pat. No. 3,085,935 may be used. Other methods can be used to produce the compound and both more and less catalyst can be used to produce formula I.

For the above reaction, R is methyl, ethyl, C _{1 -10-alkyl} (linear or branched), alkenes (linear or branched), alkynes, n- propyl, i- propyl, n- butyl, i- butyl, substituted And unsubstituted aryl moieties and substituted and unsubstituted benzyl moieties. R may also be (CH ₂ ) _n -MR ₂ , where n is a number from 1 to 6, M is an organometallic compound such as tin, silicon, or germanium, and R ₂ is propyl, butyl, or any It is selected from the group consisting of alkyl compounds of.

It may also be desirable to convert iodide salts to chloride salts. This conversion can be achieved by elution and equilibrated size exclusion (molecular sieve) chromatography with a suitable solvent containing excess ammonium chloride. Column eluents containing chloride salts, such as ammonium iodide byproducts, can be obtained by evaporation of the solvent. The resulting product should be substantially free of iodide salts. Alternatively, the chloride salt of formula I can be obtained directly by reacting the alkyochloride salt of 2,6-lutidine with the aldehyde of formula VI in the presence of a secondary amine such as piperidine.

Alternatively, the compound can be prepared by dissolving 2,6-lutidine ethiodide in methanol and then slowly bubbling anhydrous HCl (220 g) into the solution. An ice / H ₂ O bath can be used to keep the reaction below 30 ° C. After all HCl is added, the reaction is stirred overnight at room temperature. After stirring, the reaction is concentrated to near dryness and rediluted with 1000 mL of fresh methanol. Ethiodide can be converted to the desired etochloride by bubbling anhydrous HCl into the mixture. After 10 minutes of stirring, the reaction was concentrated to dryness on a rotary evaporator and placed on a high vacuum manifold for final drying.

The present invention has surprisingly confirmed that the chloride salt has increased stability compared to the iodide salt. Other methods known in the art can be used to convert the salts into UV blocker or surfactant salts.

Formula A-Stilvajan p-aminobenzoate salt

; And

Formula B-Stilvajan Dodecyl Sulfate Salt (Stilvajan Lauryl Sulfate Salt)

"Salt" also refers to substituted benzophenones such as 2,4-dihydroxy benzophenone, substituted benzotriazoles such as 2- (2-hydroxy-5'-methylphenyl) benzotriazole, ethyl 2-cyano Substituted acrylates such as -3,3-diphenyl acrylate, and salicylates such as 5-butyl phenyl salicylate.

The salt may comprise a sunscreen or surfactant. As used herein, "ultraviolet blocker" means all "photosensitive materials" which are all compositions and materials designed to block and / or absorb ultraviolet light. The term also refers to all photoprotective agents and photoresistant agents.

As above, the compounds of the present invention can be used for the treatment and treatment of inflammation, agricultural products and industrial products.

Inflammation

The compounds have been found to inhibit one or more of lipoxygenase, cyclooxygenase, and lyso-PAF: acetyl-CoA acetyltransferase. In addition, pyridinium derivatives of this series have been found to inhibit expression of binding molecules in human umbilical cord endothelial cell monolayers at surprisingly low concentrations, indicating that they can treat inflammation, infections and immune diseases.

Examples of inflammatory symptoms, infectious symptoms or immune diseases are those of the lungs, neck, mouth, joints, eyes, nose, intestines, and skin; Inflamed tissue is particularly associated with infiltration of white blood cells. Symptoms of the lung include asthma, adult respiratory distress syndrome, bronchitis and cystic fibrosis, which may additionally or alternatively be associated with intestines or other organs. Throat symptoms include laryngitis and oropharyngeal mucositis. Symptoms of the mouth include gumitis and periodontitis. Symptoms of joints include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritis symptoms. Inflammatory eye symptoms include uveitis (including iris) and conjunctivitis. Inflammatory nasal symptoms include rhinitis and chronic rhinosinusitis. Colorectal inflammatory conditions include Crohn's disease, ulcerative colitis and terminal proctitis. Skin diseases include diseases associated with cell proliferation such as psoriasis, eczema and dermatitis (whether or not of allergic origin), and allergic-induced itching such as itching. Other inflammatory symptoms and immune disorders include tissue necrosis in chronic inflammation.

The present invention also provides a method of preventing or treating an inflammatory condition or an immune disease in a mammal, such as a human, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable solvate thereof.

In another embodiment of the invention, the use for use in medical treatment; In particular, there is provided a compound of formula I, or a pharmaceutically acceptable solvate thereof, for use in the prevention or treatment of inflammatory, allergic or immune diseases in a mammal such as a human.

In addition, the compounds of formula I have been found to have anti-infective activity against certain bacteria, yeasts and fungi. This activity was unpredictable and suggests the utility of the treatment of local bacterial, yeast and fungal infections with the compounds of formula I. The infection is Staphylococcus aureus (Staphylococcus aureus) and Streptococcus (Streptococcus) strain, for example, ACF jeneseu (pyogenes), and yeast strains Candida albicans (Candida albicans), Candida Tropical faecalis (Candida to tropicalis) and the saccharide comprises a My process Sergio bicyclic Ke (Saccharomyces cervisciae), also include the following fungal strains: Cryptococcal kusu neo formate only switch (Cryptococcus neoformans), Aspergillus Fu Micah Tuscan (Aspergillus fumigatus), Aspergillus Plastic bus (Aspergillus flavus), Rizzo Perth Ari Hebrews Chargers (Rhizopus arrihizus ), Fusarium solani solani ), Mamans Microsporidium Canis ( Microsporidium) canis ), Microsporidium gypseum , Trichophytonequinium (Tree chophyton equinium ), trichophyton mentagrofit (tree chophyton mentagrophyt ), trichophyton rubrum and Epidermophyton floccsum ).

The amount of the compound of formula I, or a pharmaceutically acceptable solvate thereof, necessary to achieve the desired biological effect will be determined by a number of factors such as the intended use, means of administration, and recipient. A typical daily dose for the treatment of septic shock can be expected to be in the range of, for example, 0.005 mg / kg-100 mg / kg, preferably 0.05-50 mg / kg, and most preferably 0.5-20 mg / kg. . The dosage may be administered in a single unit dose, in multiple discrete unit doses or in a continuous infusion. Intravenous administration can be expected in the range of 0.0025 mg / kg to 50 mg / kg and will generally be administered by infusion. Similar dosage forms may be used for the treatment of other disease states. The amount of compound to be administered to the subject's lungs by the aerosol should be sufficient to achieve a concentration on the subject's airway surface liquid of about 2 to 1000 μM.

Thus, in another aspect of the invention, there is provided a pharmaceutical composition comprising as an active ingredient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutical carrier or recipient. The pharmaceutical composition can be used for the prevention and treatment of inflammatory symptoms, allergic symptoms, infectious symptoms, and immune diseases. The carrier should be pharmaceutically acceptable to the recipient and compatible with the other ingredients in the composition, i.e. should not adversely affect it. The carrier may be solid or liquid and is preferably formulated into a unit dosage formulation, such as a tablet which may comprise from 0.05 to 95% by weight of active ingredient. If desired, other physiologically active ingredients can also be incorporated into the pharmaceutical compositions of the present invention.

Possible formulations include those suitable for topical, nasal and inhalation administration including oral, buccal, rectal, and skin. The most suitable means of administration for a particular patient will depend on the nature and severity of the condition to be treated and the nature of the active ingredient, but if possible, topical administration, for example, for the treatment of local dermatitis or itching, will be preferred. However, inhalation will be the preferred route of administration for the treatment of symptoms such as asthma.

Formulations suitable for oral administration will be presented in discrete units such as tablets, capsules, cachets, lozenges, each containing a predetermined amount of active ingredient; As a powder or granules; As a solution or a suspension in an aqueous or non-aqueous liquid; Or water-in-oil or oil-in-water emulsions.

Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound in the active compound and generally flavored bases such as sugars and acacia or tragacanth and pastilles, such as gelatin and glycerin or sucrose acacia. Include.

Formulations suitable for rectal administration are preferably provided as unit dose suppositories comprising the active ingredient in at least one solid carrier which forms a suppository base such as cocoa butter.

Formulations suitable for topical or intranasal administration include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils. Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycol, alcohols, DMSO and mixtures thereof. Generally the active ingredient is present in the formulation at a concentration of 0.1 to 15% w / w.

The formulations of the present invention are prepared by any suitable method, generally by homogeneously mixing the active ingredient with the liquid or finely divided solid carrier or both in the required proportions and then, if necessary, shaping the resulting mixture into the desired form. Can be.

For example, tablets may be compressed by compacting a homogeneous mixture comprising the active ingredient and one or more optional ingredients such as binders, lubricants, inert diluents, or powders or granules of surface active dispersants, or by homogenizing the powdered active ingredient and inert liquid diluents. It can be prepared by molding the mixture.

Aqueous solutions are generally prepared by dissolving the active ingredient in saline to which cyclodextrin is added.

Formulations suitable for administration by inhalation include fine particle dust and mist which can be produced by various forms of metered dose pressure aerosols, nebulizers, or means of a pulverizer.

For pulmonary administration through the mouth, the particle size of the powder or droplets is generally in the range of 0.5-10 μm, preferably 1-5 μm to ensure delivery to the bronchial paper. For nasal administration, the particle size is preferably in the range of 10-500 μm to ensure retention in the nasal cavity.

Quantitative inhalers are generally pressurized aerosol dispersers comprising a suspension or solution formulation of the active ingredient in a liquefied propellant. During use, the device releases the formulation through a valve quantified to deliver a quantitative, typically 10 to 150 μl, to produce a fine particle spray comprising the active ingredient. Suitable propellants include certain chlorofluorocarbon compounds such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof. The formulation may further comprise one or more cosolvents such as ethanol and fatty acid surfactants such as oleic acid or sorbitan trioleate, antioxidants and suitable flavoring agents.

A nebulizer is a commercially available device that transforms a solution or suspension of the active ingredient into an aerosol mist by the acceleration of compressed gas, generally air or oxygen, or by ultrasonic oscillation through a narrow venturi orifice. Suitable formulations for use in nebulizers consist of the active ingredient in a liquid carrier and comprise up to 40% w / w of the formulation, preferably up to 20% w / w. The carrier is generally isotonicized into the body fluid by the addition of water or a dilute water soluble alcohol solution, preferably sodium chloride, for example. Optional additives include preservatives such as methyl hydroxy-benzoate, antioxidants, flavors, volatile oils, buffers and surfactants if the formulation is not aseptically produced.

Suitable formulations for administration by inhalation include fine powders that can be delivered by inhaler or inhaled into the nasal cavity in the manner of nasal inhalation. In the inhaler, the powder is contained in a capsule or cartridge, generally made of gelatin or plastic, penetrated or opened in situ and the powder is introduced through the device upon inhalation or delivered by a manually operated pump. The powder used in the inhaler consists either of the active ingredient alone or of a powder mixture comprising the active ingredient, a suitable powder diluent such as lactose, and an optional surfactant. The active ingredient generally comprises from 0.1 to 100 w / w of the formulation.

Thus, according to another aspect of the present invention there is provided the use of a compound of formula I or a pharmaceutically acceptable solvate thereof for use in the manufacture of a medicament for the prevention or treatment of inflammatory symptoms or immune diseases.

In addition, the present invention can provide a microcapsule comprising a capsule wall film of a synthetic resin and an ultraviolet absorbent having an average particle size of 0.1 to 3 μm and an organic solvent enclosed therein. The absorbent may block or inhibit ultraviolet rays.

Agriculture

In addition, the compounds according to the present invention can be used for powdered powder and rust, pyrenophora, rhynchosporium, tapesia, fusarium and leptosphaeria fungi, In particular, it is effective against lesions of monocotyledonous plants, such as cereals including wheat and barley. In addition, the compounds according to the invention are also effective against fluffy white powdery species, powdery powdery mildew, leaf point disease and rust disease in dicotyledonous plants.

The amount of the compound of the present invention to be administered depends on the compound to be used, the substance to be treated (substrate, plant, soil, seed), the type of treatment (eg spraying, dusting, seed dressing), the purpose of treatment (prevention or healing), the fungus to be treated and And / or depend on various factors such as the type of bacteria and the time of administration.

Fungicide and / or fungicide mixtures may be used in various crops or their seeds, in particular wheat, rye, barley, oats, rice, corn, grass, cotton, soybeans, coffee, sugarcane, fruits and ornaments, in horticulture and grape cultivation. Of interest to vegetables, such as cucumbers, beans and gourds, and to field crops such as potatoes, peanuts, tobacco and beets, are of interest to control a number of fungi and / or bacteria.

"Control" means reduced, suppressed, reduced, suppressed, interrupted, and the like.

The mixture is applied by treating fungal and / or bacterial or seed, substances threatened by plant or fungal attack, or soil using fungicidal and / or bactericidal effective amounts of the active ingredient.

The agent may be applied before or after infection of the substance, plant or seed by fungi and / or bacteria.

When applied to plants the compound of formula I is from 20 to 2000 g / ha, generally from 20 to 1000 g / ha, from 25 to 250 g / ha, generally from 50 to 150 g / ha, such as 75, 100 , 125 or 150 g / ha.

In agricultural practice the rate of infusion of the compound depends on the type of effect desired and the amount of active ingredient per hectare ranges from 0.02 to 3 kg.

When active widows are used for seed treatment, a ratio of 0.001 to 50 g per kg seed, and generally 0.01 to 10 g per kg seed, is generally sufficient.

The compositions of the present invention may be used in any conventional form, such as in the form of twin packs, disposable granules, flowable formulations, emulsion thickeners or wet powders or surfactants (eg, sodium lauryl sulfate and sodium lauryl sulfate salt) It may be combined with agriculturally acceptable adjuvant. The composition can be prepared by conventional methods, for example by mixing the active ingredient with a suitable adjuvant (optionally other formulation ingredients such as diluents or solvents and surfactants). In addition, conventional sustained release formulations may be used when long lasting efficacy is intended.

Particular formulations applied in the form of sprays, in particular water dispersible thickeners or wettable powders, include wetting and dispersing agents such as formaldehyde and naphthalene sulfonates, alkyllaurylsulfonates, lignin sulfonates, fatty alkyl sulfonates, and ethoxylated alkyls. Condensation products of phenols and ethoxylated fatty alcohols.

Seed dressing formulations are applied to the seeds in a known manner using diluents suitable for the mixtures and seed dressing formulations of the invention, such as aqueous suspensions or diluents in dry powder form with good adhesion to the seeds. Such seed dressing formulations are known in the art. Seed dressing formulations may comprise a single active ingredient or a mixture of active ingredients in encapsulated form, eg, sustained release capsules or microcapsules.

In general, the formulation comprises 0.01 to 90% by weight of active agent, 0 to 20% by weight of agriculturally acceptable surfactant and 10 to 99.99% by weight of solid or liquid adjuvant, wherein the active agent is at least of formula (I) Compounds, and optionally other active agents, in particular microbids or preservatives and the like. Concentrated forms of the composition generally comprise from 2 to 80% by weight, generally 5 to 70% by weight of active agent. Injectable forms of the formulation may, for example, comprise from 0.01 to 20% by weight, generally from 0.01 to 5% by weight of active agent. While commercial products are generally formulated as concentrates, end consumers will typically use diluent preparations.

In addition, the color of the compounds of the present invention can be removed by a kind of "bleaching". It is well known in the art that peroxidases act on various amino and phenolic compounds to produce color (see, eg, B.C. Saunders et al., Peroxidase, London, 1964, p. 10ff.). Because of this, surprisingly, peroxidases (and certain oxidases) can affect the coloring agent in solution so that dye transfer can be suppressed. Mechanisms governing the activity of these enzymes that affect stain transfer inhibition have not been found, but at present the enzymes reduce hydrogen peroxide or molecular oxygen, oxidize colored substances (donor substrates) dissolved or dispersed in the wash liquid, It is contemplated to work by providing a material which does not produce colorless material or which is not absorbed by cloth or building material.

In addition, liquid compositions according to the invention can be formed and mixed with and / or diluted with excipients. If the excipient acts as a diluent, it may be a solid, semisolid or liquid substance that acts as a vehicle, carrier, or medium for the composition. Various suitable excipients will be understood by those skilled in the art and may be referred to National Formulary , 19: 2404-2406 (2000), the disclosures of pages 2404-2406 of which are incorporated herein by reference in their entirety. Preferred excipients include butanedioal and EDTA. Examples of suitable excipients include, but are not limited to, starch, gum arabic, calcium silicate, microcrystalline cellulose, methacrylate, shellac, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. . Aqueous media include the active ingredient or components, one or more surfactants sufficient to dissolve or suspend the active ingredient consistently through a large amount of the medium and other manufacturing additives known in the art. The other preparation additives include granulation-binding agents such as gelatin; Natural gums such as acacia, tragacanth; Starch, sodium alginate, sugar, polyvinylpyrrolidone; Cellulose derivatives such as hydroxypropylmethyl cellulose and polyvinyloxoazolidone; Pharmaceutical fillers such as lactose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, calcium sulfate, dextrose, mannitol, sucrose; If necessary, tableting lubricants such as calcium and magnesium stearate, stearic acid, talc, sterotex (alkaline stearate). “Aqueous medium” for one component of one embodiment of the invention is used within the practice of the art. Primarily refers to a water medium to which a solvent is added which, if necessary, can be mixed with water such as isopropanol or ethanol to support the active ingredient.

industry

The compounds of the present invention can be used to treat all sites where filamentous fungi, fungi and bacteria grow. Examples include wood, air ducts, plates, decks, pipes, stucco, tiles, paint, insulation , Roofs, building materials, metals, computer parts, food packaging, substrates, and the like.

Another embodiment of the present invention includes encapsulated stiletto compounds. As used herein, "microcapsules" is intended to mean single molecules, encapsulated individual particles, multiparticles, liquid multicore and homogeneously dissolved active compounds. The encapsulation method can provide a water soluble or oil soluble tracer encapsulated in a shell matrix of a water soluble or oil soluble material. The microencapsulated active ingredient can be protected from oxidation and hydration and can be released by dissolving, breaking, biodegrading, or dissolving the surrounding shell matrix or by slowly diffusing the active ingredient through the matrix. Microcapsules are generally 1 to 2000 microns in size, and smaller or larger sizes are known in the art.

The compounds of the present invention may be disposed in the form of hollow fibers used for microcapsules or diffusion. In addition, they may be dispersed in the polymerizable material or contained as a liquid.

The active ingredient may be disposed together with the compound of the present invention in microcapsules. Examples of the active ingredient having repulsive activity may include triethylene glycol monohexyl ether and N, N-diethyl-m-triamide. Examples of the active ingredient having aromatic activity is the Raney include all, remote Nene, benzyl alcohol, C _{6 -20} hydrocarbon, ethers, aldehydes and alcoholic compounds. Examples of such active ingredients having an insecticidal effect include insecticides such as salitione, diazinon and chlorpyriphos and fungicides such as thiophanate-methyl and captan.

The construct can be encapsulated as desired in the case of a phase change material. The encapsulation construct may be further encapsulated in a microcapsule. The microcapsules contain a wide variety of materials such as polyethylene, polypropylene, polyester, polyvinyl chloride, tristarch acetate, polyethylene oxide, polypropylene oxide, polyvinylidene chloride or fluoride, polyvinyl alcohol, polyvinyl acetate, urethane, Polycarbonates, and polyacetones. More details on microencapsulation are disclosed in US Pat. Nos. 5,589,194 and 5,433,953, which are incorporated herein in their entirety. Microcapsules suitable for use in the base material of the present invention have a diameter of about 1.0 to 2,000 microns.

No specific limitation is imposed on the form of supporting the active ingredient. In other words, there are various forms for supporting the active ingredient by the support mixture. Specific examples include microcapsules wherein the surface of the active ingredient is applied with a support mixture; And a product processed into the desired form, each obtained by kneading the active ingredient in the support mixture or by forming a homogeneous solution of the support mixture, or by dispersing the active ingredient in the support mixture, removing the solvent and the like, and The dispersion is processed into the desired form such as single molecule, liquid, sphere, sheet, film, rod, pipe, needle, tape or chip. In addition, the processed product having a surface coated with a barrier layer for controlling the release of the active ingredient and a surface coated with an adhesive to improve usability may be given as an example. As a further example, one obtained by filling an active ingredient in a capillary processed support mixture, heat sealing both ends of the capillary, and then encapsulating the active ingredient therein; And cutting the center of the capillary into two pieces, whereby each has one end of the opening.

The container formed of the support mixture has the active ingredient enclosed therein as a liquid phase to ensure a constant release capability over a long period of time. As in the above form, a tube-, bottle- or bag-shaped container is generally used.

When the mixture is formed into the vessel, the sustained release layer preferably has a thickness of at least 0.002 mm for stable sustained release. If the sustained release layer has a thickness of 0.002 mm or more, no problem occurs, but 0.005 mm to 5 mm can be used. If the thickness exceeds 5 mm, the amount of the compound released tends to be too small.

For solids, the release surface area of the sustained release formulation formed into the vessel is preferably at least 0.001 cm 2. A range of 0.01 to 1 cm 2 can be used.

If the active ingredient is enclosed and contained in a container of a sustained release formulation formed of a support mixture, the active ingredient may be enclosed little by little. The loading may be 0.5 to 5 mg, and may be 1 mg, 2 mg, 3 mg or 4 mg.

As the form of the container formed from the support mixture, tubes, bottles and bags can be used. In the case of tube-shaped preparations, those having an inner diameter of 0.4 mm to 10 mm can be used. Internal diameters of 0.4 mm or less make it difficult to fill the active ingredient in the container, and internal diameters of 10 mm or more make it difficult to perform encapsulation. Bottle-shaped formulations are formed by blow molding or injection molding and generally have an internal volume of 0.1 to 200 mL. Bottles with an internal volume of 0.1 mL or less cannot be easily formed, and bottles with an internal volume of 200 mL or more are uneconomical because there is a large difference between the amount and the internal volume of the active ingredient filled therein. In the case of a bag-form preparation, the amount of active ingredient filled in the bag is preferably 1 mg to 100 g.

Biodegradable sustained release formulations according to the first group of the invention can be added with pigments or dyes, or various stabilizers such as ultraviolet absorbers / blockers, to the support mixture in order to improve the weather resistance by maintaining intrinsic performance during their application. . Alternatively, it is possible to add the mixture to the active ingredient enclosed in a container formed from the support mixture.

As used herein, "controlled release" means releasing bioactive material at a preselected or desired rate. The speed will vary depending on the application. Preferred rates include rapid or immediate release profiles and delayed, sustained or continuous release profiles. Combinations of release patterns, such as initially suppressed release of bioactive materials and then lower levels of sustained release, are also contemplated by the present invention.

As used herein, "living" refers to therapeutic agents such as pharmaceutical or pharmacologically active agents, such as drugs and pharmaceuticals, and other chemicals or substances useful for the treatment or prevention of prophylactic, diagnostic and symptomatic, infection and / or diseases. It includes. The compositions of the present invention are particularly effective in plants and other organisms.

According to the present invention a photo-stable UV absorber compound or blocker compound and a pyridinium salt and a biological synergistic effect having a log molar extinction coefficient of 2 to 5 for radiation having a wavelength in the range of 270 to 350 nanometers as a complete part of the shell Microcapsule disinfecting and / or fungicidal compositions are provided comprising a polyurea shell comprising a compound having a microcapsule and a microcapsule having a liquid filler capable of slowly penetrating the shell.

As used herein, "photosensitive material" means all compositions and materials designed to block and / or absorb ultraviolet light. The term also means all photoprotective and photoresistant agents.

As used herein, "surfactant" means all compositions including surfactant salt compositions capable of forming emulsions, micro-emulsions, suspensions and the like.

The intact microcapsule composition may comprise 60-90 percent liquid filler and 40-10 percent shell wall, the liquid filler having 5-40 percent pyridium salt, 25-50 percent biological synergistic material. And 20-40 percent of an organic solvent miscible with water and the shell comprises 0.5-20 percent of the light stable ultraviolet absorbent compound as a constituent part (all percentages are based on the weight of the intact microcapsule composition).

Because of the partial pressure of the pyridium salt surrounding the microcapsules, the pyridium salt is present inside the microcapsules and the composition is filled and present in a reservoir, ie in a closed container. When the product is applied as a fungicide and / or fungicide, the pyridium salt is released slowly (the actual rate of release depends on the thickness and porosity of the capsule wall). The pyridium salt is chemically stable during storage and after application until it penetrates the capsule wall. It is then available as a fungicide and / or fungicide until degraded. Because the filler slowly penetrates into the cell walls, the microcapsule product can be stored for extended periods of time (eg, 6 months or longer) with a long bactericidal and / or fungicidal effect period.

Suitable fill stabilizers absorb ultraviolet light in the range of 270-350 nanometers and convert to harmless forms. The material has a high absorption coefficient (eg, log molar extinction coefficient of about 2 to 5) in the vicinity of the ultraviolet light of the spectrum but only minimal absorption in the visible portion of the spectrum. The material does not exhibit any substantial chemical reaction with the isocyanate groups and the primary amine groups of the shell forming the compound during the microencapsulation process. Compounds that can be used as fill stabilizers include substituted benzophenones such as 2,4-dihydroxy benzophenone, 2-hydroxy-4-methoxy benzophenone, 2-hydroxy-4-octyloxy benzophenone, and the like; Benzotriazoles such as 2- (2-hydroxy-5'-methylphenyl) benzotriazole, 2- (3 ', 5'-diallyl-2'-hydroxyphenyl) benzotriazole and the like; Substituted acrylates such as ethyl 2-cyano-3,3-diphenyl acrylate, 2-ethylhexyl-2-cyano-3,3-diphenyl acetate and the like; Salicylates such as phenyl salicylate, 5-butyl phenyl salicylate and the like; And acetatekel organic compounds such as acetatekel bis (octylphenol) sulfide and the like. For further examples of each class of fill stabilizers, see Kirk-Othmer, Encyclopedia of Chemical Technology. The fill stabilizer may comprise 5% by weight, and generally from 0.01 to 2% by weight of the microcapsule composition.

In addition, embodiments of the present invention provide a method of controlling fungal and bacterial activity by contacting fungi and bacteria with a composition comprising an effective level of stilbark compound as described above. The contact can be carried out directly, for example by spraying the compound in the form of a spray into the air. Alternatively, the compositions of the present invention may be provided in a sheet material (microcapsule coated or infused tape) that carries microcapsules, which can be placed in various other forms, such as in areas where fungi and bacteria can grow. have.

Other embodiments of the present invention may include microcapsules having a heat sensitive material excellent in protective stability, particularly in light resistance, and an ultraviolet absorber enclosed therein, which is applicable to various fields. Preferred constructs that may be present in the base material include materials that can absorb heat and protect the underlying material from overheating. Thermal energy is absorbed by the phase change of the material without causing an increase in the temperature of the material. Suitable phase change materials include paraffinic hydrocarbons, ie side chain hydrocarbons represented by the formula C _n H _{n +2} , where n can range from 13 to 28. Other compounds suitable as phase change materials are 2,2-dimethyl-1,3-propane diol (DMP), 2-hydroxymethyl-2-methyl-1,3-propane diol (HMP) and similar compounds. In addition, fatty esters such as methyl palmitate can be used. Phase change materials that can be used include paraffinic hydrocarbons.

Thermally sensitive recording materials are well known and thermally contact the two chromogenic materials with each other using a color that forms a reaction between a colorless or light colored basic dye and an organic or inorganic color acceptor to obtain a recorded image. The thermally sensitive materials have been adapted for use with relatively inexpensive, simple and easy-to-maintain recording devices, and thus have been found to have a wide range of applications as recording media for facsimile systems, various computers and the like. In order to improve the light resistance of the heat sensitive recording material, finely decomposed ultraviolet absorbers or blocking agents may be added to the heat sensitive recording layer or protective layer.

Another embodiment of the present invention is to provide microcapsules which have excellent ultraviolet absorbent retention properties, are difficult to break at normal pressure, and have excellent ultraviolet absorbing efficacy.

Embodiments of the invention may include a substrate, a recording layer formed on the substrate and comprising a colorless or light colored basic dye and a color receptor, and a protective layer formed on the recording layer, wherein the recording material is Microcapsules having an ultraviolet absorber encapsulated therein and having substantially no color forming ability are introduced into the protective layer.

The present invention also provides a microcapsule comprising a ultraviolet absorber and, if necessary, an organic solvent enclosed therein and having a synthetic resin and a capsule wall film with an average particle size of 0.1 to 3 μm.

The following are examples of ultraviolet absorbers that can be used in the present invention.

Salicylic acid type ultraviolet absorbers such as phenyl salicylate, p-tert-butylphenyl salicylate, p-octylphenyl salicylate; 2,4-dihydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-octyloxybenzophenone, 2-hydroxy-4-dodecyloxybenzophenone, 2,2 Benzo such as '-dihydroxy-4-methoxybenzophenone, 2,2,'-dihydroxy-4,4'-dimethoxybenzophenone, 2-hydroxy-4-methoxy-5-sulfobenzophenone Phenone type ultraviolet absorbers; Cyanoacrylate type ultraviolet absorbers such as 2-ethylhexyl 2-cyano-3,3-diphenyl-acrylate and ethyl 2-cyano-3,3-diphenylacrylate; Bis (2,2,6,6-tetramethyl-4-piperidyl) sebacate, bis (2,2,6,6-tetramethyl-4-piperidyl) succinate, bis (1,2, Hindered amine types such as 2,6,6-pentamethyl-4-piperidyl) 2- (3,5-di-tert-butyl-4-hydroxybenzyl) -2-n-butyl malonate Ultraviolet absorbers; 2- (2'-hydroxyphenyl) benzotriazole, 2- (2'-hydroxy-5'-methylphenyl) benzotriazole, 2- (2'-hydroxy-5-tert-butylphenyl) benzotria Sol, 2- (2'-hydroxy-3 ', 5'-di-tert-butylphenyl) benzotriazole, 2- (2'-hydroxy-3'-tert-butyl-5'-methylphenyl)- 5-chlorobenzotriazole, 2- (2'-hydroxy-3 ', 5'-di-tert-butylphenyl) -5-chlorobenzotriazole, 2- (2'-hydroxy-3', 5 '-Di-tert-butylphenyl) -5-tert-butylbenzotriazole, 2- (2'-hydroxy-3', 5'-di-tert-amylphenyl) benzotriazole, 2- (2 ' -Hydroxy-3 ', 5'-di-tert-amylphenyl) -5-tert-amylbenzotriazole, 2- (2'-hydroxy-3', 5'-di-tert-amylphenyl)- 5-methoxybenzotriazole, 2- [2'-hydroxy-3- (3 ", 4", 5 ", 6" -tetrahydrophthalimido-methyl) -5'-methylphenyl] benzotriazole , 2- (2'-hydroxy-5'-tert-octylphenyl) benzotriazole, 2- (2'-hydroxy-3'-sec-butyl 5'-tert-butylphenyl) benzotriazole, 2 -(2'-hydroxy C-3'tert-amyl-5'-phenoxyphenyl) -5-methylbenzotriazole, 2- (2'-hydroxy-5'-n-dodecylphenyl) benzotriazole, 2- (2 ' -Hydroxy-5'-sec-octyloxyphenyl) -5-phenylbenzotriazole, 2- (2'-hydroxy-3'-tert-amyl-5'-phenylphenyl) -5-methoxybenzotria Benzotriazole type ultraviolet absorbers which are solid at ordinary temperatures such as sol, 2- [2'-hydroxy-3 ', 5'-bis (α, α-dimethylbenzyl) phenyl] benzotriazole; 2- (2'-hydroxy-3'-dodecyl-5'-methylphenyl) -benzotriazole, 2- (2'-hydroxy-3'-undecyl-5'-methylphenyl) -benzotriazole, 2- (2'-hydroxy-3'-tridecyl-5'-methylphenyl) -benzotriazole, 2- (2'-hydroxy-3'-tetradecyl-5'-methylphenyl) -benzotriazole, 2- (2'-hydroxy-3'-pentadecyl-5'-methylphenyl) -benzotriazole, 2- (2'-hydroxy-3'-hexadecyl-5'-methylphenyl) -benzotriazole, 2- [2'-hydroxy-4 '-(2 "-ethylhexyl) oxyphenyl] -benzotriazole, 2- [2'-hydroxy-4'-(2" -ethylheptyl) oxyphenyl]- Benzotriazole, 2- [2'-hydroxy-4 '-(2 "-ethyloctyl) oxyphenyl] -benzotriazole, 2- [2'-hydroxy-4'-(2" -propyloctyl) Oxyphenyl] -benzotriazole, 2- [2'-hydroxy-4 '-(2 "-propylheptyl) oxyphenyl] -benzotriazole, 2- [2'-hydroxy-4'-(2" -Propylhexyl) oxyphenyl] -benzotriazole, 2- [2'-hydroxy-4 '-(1 "-ethylhexyl) oxyphenyl] -benzotriazole, 2- [2'-high Hydroxy-4 '-(1 "-ethyloctyl) oxyphenyl] -benzotriazole, 2- [2'-hydroxy-4'-(1" -propyloctyl) oxyphenyl] -benzotriazole, 2- [2'-hydroxy-4 '-(1 "-propylheptyl) oxyphenyl] -benzotriazole, 2- [2'-hydroxy-4'-(1" -propylhexyl) oxyphenyl] -benzotria Sol, 2- (2'-hydroxy-3'-sec-butyl-5'-tert-butylphenyl) -5-n-butylbenzotriazole, 2- (2'-hydroxy-3'-sec- Butyl-5'-tert-butylphenyl) -5-tert-butylbenzotriazole, 2- (2'-hydroxy-3'-sec-butyl-5'-tert-butylphenyl) -5-n-pentyl Benzotriazole, 2- (2'-hydroxy-3'-sec-butyl-5'-tert-pentylphenyl) -5-tert-butylbenzotriazole, 2- (2'-hydroxy-3'- sec-butyl-5'-tert-pentylphenyl) -5-n-butylbenzotriazole, 2- (2'-hydroxy-3 ', 5'-di-tert-butylphenyl) -5-sec-butyl Benzotriazole, 2- (2'-hydroxy-3 ', 5'-di-tert-pentylphenyl) -5-sec-butylbenzotriazole, 2- (2'-hydroxy-3'-tert- Butyl-5'-tert-pentylphenyl) -5-sec-butylbenzotria , 2- (2'-hydroxy-3 ', 5'-di-sec-butylphenyl) -5-chlorobenzotriazole, 2- (2'-hydroxy-3', 5'-di-sec- Butylphenyl) -5-methoxybenzotriazole, 2- (2'-hydroxy-3 ', 5'-di-sec-butylphenyl) -5-tert-butylbenzotriazole, 2- (2'- Hydroxy-3 ', 5'-di-sec-butylphenyl) -5-n-butylbenzotriazole, octyl 5-tert-butyl-3- (5-chloro-2H-benzotriazol-2-yl) 4-hydroxybenzene-propionate, methyl 3- [3-tert-butyl-5- (2H-benzotriazol-2-yl) -4-hydroxyphenyl] propionate and polyethylene glycol (molecular weight: Benzotriazole type sunscreens that are liquid at normal temperatures, such as condensates of about 300). Of course, the sunscreen is not limited to the material and may be used as a mixture of at least two compounds if necessary.

Although the amount of the ultraviolet absorbent used is not particularly limited, the amount can be adjusted to 10 to 500 parts by weight, and generally 20 to 250 parts by weight, based on the active ingredient.

Microcapsules for use in the present invention can be prepared by a variety of known methods. It is generally prepared by emulsifying and dispersing a core material (oily liquid) comprising an ultraviolet solvent and, if necessary, an organic solvent in an aqueous medium, and forming a wall film of high molecular weight material around the resulting oily water droplets.

Examples of useful high molecular weight materials for forming wall films of microcapsules include polyurethane resins, polyurea resins, polyamide resins, polyester resins, polycarbonate resins, aminoaldehyde resins, melamine resins, polystyrene resins, styrene-acrylates Copolymer resins, styrene-methacrylate copolymer resins, gelatin, polyvinyl alcohol, and the like. In particular, among these resins, microcapsules having wall films of synthetic resins, in particular polyurea resins, polyurethane resins and aminoaldehyde resins, have excellent ultraviolet absorber retention and high temperature resistance and thus serve as protective layers to prevent adhesion to the thermal head. Has a significant additional effect of supplying the function of the pigment to be injected. Moreover, microcapsules with wall films of polyurea resins or polyurethane resins have a lower index of refraction, are spherical, and therefore are present in large quantities in the protective layer compared to microcapsules with wall films of other materials and conventional pigments. Even if it does not reduce the recording image density (so-called whitening) due to irregular reflection of light, it can be preferably used. In addition, polyurea resins and polyurethane resins are more flexible than aminoaldehyde resins, and therefore polyurea resins and polyurethane resins are generally used as wall films for microcapsules in which they are used under high pressure conditions. On the other hand, since microcapsules having a wall film made of aminoaldehyde resin can be prepared by adding a wall forming material after emulsification of the core material, the microcapsules can be adjusted in thickness regardless of the particle size of the emulsion. Has the advantage that it can.

In addition, the present invention may include an organic solvent together with the ultraviolet absorbent. The organic solvent is not particularly limited and various hydrophobic solvents may be used in the field of pressure sensitive manifold papers. Examples of organic solvents include phosphates such as tricresyl phosphate and octyldiphenyl phosphate, phthalates such as dibutyl phthalate and dioctyl phthalate, carboxylates such as butyl oleate, various fatty acid amides, diethylene glycol dibenzoate, mono Alkylated benzene such as alkylated naphthalene, 1-methyl-1-phenyl-1-tolylmethane, 1-methyl-1-phenyl-1-xylylmethane, 1-phenyl-1-tolylmethane, such as isopropylnaphthalene and diisopropylnaphthalene , Alkylated biphenyls such as isopropyl biphenyl, trimethylolpropane triacrylate, acrylates such as polyols and unsaturated carboxylic acids, chlorolated paraffins and kerosine. The solvents may be used alone or in mixture of two or more. Among the hydrophobic media having a high boiling point, tricresyl phosphate and 1-phenyl-1-tolylmethane are preferred because they show high solubility with respect to the ultraviolet absorber used in the present invention. In general, the lower the viscosity of the core material, the smaller the particle size resulting from the emulsification and the narrower the particle size distribution, whereby a solvent having a lower boiling point can be used together to lower the viscosity of the core material. Examples of such low boiling solvents are ethyl acetate, butyl acetate, methylene chloride and the like.

The amount of the organic solvent used will be appropriately adjusted according to the kind and amount of ultraviolet absorber used and the kind of organic solvent, and is not particularly limited. For example, in the case of using a ultraviolet absorber that is liquid at ordinary temperatures, an organic solvent is not necessarily used. However, when using a ultraviolet absorber that is a solid at normal temperature, since the ultraviolet absorber is preferably dissolved completely in the microcapsules, for example, in the case of microcapsules of polyurea resin or polyurethane resin, the amount of organic solvent is organic solvent, ultraviolet Based on the mixed amount of absorbent and wall forming material, it is generally adjusted to 10 to 60% by weight, or 20 to 60% by weight. In addition, in the case of microcapsules of aminoaldehyde resins, the amount of the organic solvent is usually adjusted to 50 to 2000% by weight of the ultraviolet absorbent, generally 100 to 1000% by weight.

Although the amount of capsule wall-forming material used is not particularly limited, long-term preservation causes the organic solvent in the microcapsules to leak out to reduce the expected effect or to heat sensitive recording materials and other materials including the microcapsules used. It is preferable to use a larger amount of wall forming material than in the case of conventional microcapsules used in pressure sensitive recording materials and the like, since it tends to give adverse effects. Thus, for example when using microcapsules of polyurea resins or polyurethane resins, the wall forming material is preferably 20 based on the mixing amount of the three compounds, i.e., the organic solvent, the ultraviolet absorber and the wall forming agent used as necessary. To 70% by weight, more preferably 25 to 60% by weight. When using microcapsules of aminoaldehyde resins, the wall-forming material is generally in an amount of 30 to 300% by weight, preferably 35 to 200% by weight of the core material comprising a UV absorber as the main component and an organic solvent as required. Used in% amounts.

In addition, an absorbent may be used. Of the spectral sensitivity range (its inactive range) which prevents the exposure of microcapsules of different wavelengths without excessively reducing the sensitivity of the microcapsules in this portion of the spectral sensitivity range (its active range) in which the microcapsules are intended to be exposed. Absorbents that reduce the micronity of the microcapsules in the portion should be selected. In some cases it may be necessary to compare the absorption properties of the absorbent in the active and inactive ranges to achieve optimal exposure properties. In general, absorbents are used having an extinction coefficient of at least about 100 / M cm in the inactive range of the microcapsules and up to about 100,000 / M cm in the active range. If the absorbent is injected directly into the photosensitive composition, ideally it should not inhibit free radical polymerization and should not produce free radicals upon exposure.

The absorbent used in the present invention may be selected from among absorbents known in the photographic art. Examples of such compounds include dyes commonly used as silver halide photosensitive dyes in color photography (eg, cyanine, merocyanine, hemicyanine and styryl dyes) and ultraviolet absorbers. In addition, many colored dyes that absorb outside the desired sensitivity range of the microcapsules and do not absorb heavily within this range can be used in the present invention. Among these materials, Sudan I, Sudan II, Sudan III, Sudan Orange G, Oil Red O, Oil Blue N, and Fast Garnet GBC are examples of potentially usable compounds.

In addition, ultraviolet absorbers which may be preferred may include those selected from hydroxybenzophenone, hydroxyphenylbenzo-triazole and formamidine. The absorbents can be used alone or in combination to achieve the desired spectral sensitivity properties.

Representative examples of hydrobenzobenzophenones that can be used are 2-hydroxy-4-n-octoxybenzophenone (UV-CHEK AM-300 from Ferro Chmical Division, Mark 1413 from Argus Chemical Division, Witco Chem. Corp., and American). Cyanamid's Cyasorb UV-531 Light Absorber), 4-dodecyl-2-hydroxybenzophenone (Eastman Kodak's Eastman Inhibitor DOBP), 2-hydroxy-4-methoxybenzophenone (American Cyanamid's Cyasorb UV-24 Light) Absorber). Representative examples of hydroxybenzophenyl benzotriazoles that can be used are 2- (2'-hydroxy-5'-methylphenyl) benzotriazole (Tinuvin P from Ciba-Geigy Additives Dept.), 2- (3 ', 5' -Di-tert-butyl-2'-hydroxyphenyl) -5-chlorobenzotriazole (Tinuvin 327 from Giba-Geigy), and 2- (2-hydroxy-5-t-octylphenyl) benzotriazole ( American Cyanamid's Cyasorb UV-5411 Light Absorber). Representative examples of usable formamidines are disclosed in US Pat. No. 4,021,471 and include N- (p-ethoxy-carbonylphenyl) -N'-phenylformamidine (Givsorb UV-2 from Givaudan Corp.) do. The optimal absorbent and concentration for a particular application depends both on the absorption maximum and extinction coefficient of the absorbent candidate and on the spectral sensitivity properties of the associated photoinitiator.

In addition, the microcapsules, photosensitive compositions, image forming agents, developers, and developing techniques are disclosed in US Pat. Nos. 4,399,209 and 4,440,846, which may be incorporated by reference and used in the present invention.

In addition, the compounds according to the invention are particularly effective against powdery white powder and rust, pyrenophora, rhynchosporium, tapesia, fusarium and leptosphaeria fungi. It is effective against lesions of monocotyledonous plants such as cereals including wheat, wheat and barley. In addition, the compounds according to the invention are also effective against fluffy white powdery species, powdery powdery mildew, leaf point disease and rust disease in dicotyledonous plants.

The amount of the compound of the invention to be applied depends on the compound being used, the object to be treated (substrate), the type of treatment (e.g., splashing, dusting, seed dressing), the purpose of the treatment (preventing or healing), the type of fungi and / or bacteria to be treated and It will depend on various factors such as application time.

The medicament may be applied before or after infection of any listed material by fungi and / or bacteria.

The compound of formula I when applied to plants is associated with 20 to 2000 g / ha, generally 20 to 1000 g / ha, 25 to 250 g / ha, generally 50 to 150 g / ha, such as 75, 100 , 125 or 150 g / ha.

In industrial practice the rate of application of the mixtures depends on the type of effect desired and ranges from 0.02 to 3 kg of active ingredient per hectare.

When the active ingredient is used to treat the seed, generally 0.001 to 50 g, and generally 0.01 to 10 g per kg seed are sufficient.

The compositions of the present invention can be used in any conventional form, including surfactants such as lauryl sulfate, in the form of twin packs, disposable granules, flowable formulations, emulsion thickeners or wet powders, and industrially acceptable adjuvants. Can be combined with burnt. The composition can be prepared by conventional methods, for example by mixing the active ingredient with a suitable adjuvant (optionally other formulation ingredients such as diluents or solvents and surfactants). In addition, conventional sustained release formulations may be used when long lasting efficacy is intended.

Certain formulations applied in the form of sprays, such as water dispersible thickeners or wettable powders, include wetting and dispersing agents such as formaldehyde and naphthalene sulfonates, alkyllaurylsulfonates, lignin sulfonates, fatty alkyl sulfonates, and ethoxylated alkylphenols. And condensation products of ethoxylated fatty alcohols.

Seed dressing formulations are applied to the seeds in a known manner using diluents suitable for the mixtures and seed dressing formulations of the invention, such as aqueous suspensions or diluents in dry powder form with good adhesion to the seeds. Such seed dressing formulations are known in the art. Seed dressing formulations may comprise a single active ingredient or a mixture of active ingredients in encapsulated form, eg, sustained release capsules or microcapsules.

In general, the formulation comprises 0.01 to 90% by weight of active agent, 0 to 20% by weight of agriculturally acceptable surfactant and 10 to 99.99% by weight of solid or liquid adjuvant, wherein the active agent is at least of formula (I) Compounds, and optionally other active agents, in particular microbids or preservatives and the like. Concentrated forms of the composition generally comprise from 2 to 80% by weight, generally 5 to 70% by weight of active agent. Injectable forms of the formulation may, for example, comprise from 0.01 to 20% by weight, generally from 0.01 to 5% by weight of active agent. While commercial products are generally formulated as concentrates, end consumers will typically use diluent preparations.

In addition, the color of the compounds of the present invention can be removed by a kind of "bleaching". Moreover, when an enzyme using hydrogen peroxide or molecular oxygen for the oxidation of organic or inorganic materials, including coloring materials, is added to the wash liquor, from the compound of the invention in the dyed fabric and building materials or as a colorant in a solution of the wash liquor It has been found that by bleaching the colored material filtered from the soiled fabric and building material, it is possible to prevent the colored material in question from being deposited on other fabrics and building materials in the cleaning liquid. Generally, these enzymes are named peroxidase and oxidase, respectively. It is well known in the art that peroxidases act on various amino and phenolic compounds to produce color (see, eg, B.C. Saunders et al., Peroxidase, London, 1964, p. 10ff.). Because of this, surprisingly, peroxidases (and certain oxidases) can affect the coloring agent in solution so that dye transfer can be suppressed. Mechanisms governing the activity of these enzymes that affect stain transfer inhibition have not been found, but at present the enzymes reduce hydrogen peroxide or molecular oxygen, oxidize colored substances (donor substrates) dissolved or dispersed in the wash liquid, It is contemplated to work by providing a material which does not produce colorless material or which is not absorbed by cloth or building material.

In addition, liquid compositions according to the invention can be formed and mixed with and / or diluted with excipients. If the excipient acts as a diluent, it may be a solid, semisolid or liquid substance that acts as a vehicle, carrier, or medium for the composition. Various suitable excipients will be understood by those skilled in the art and may be referred to National Formulary , 19: 2404-2406 (2000), the disclosures of pages 2404-2406 of which are incorporated herein by reference in their entirety. Preferred excipients include butanedioal and EDTA. Examples of suitable excipients include, but are not limited to, starch, gum arabic, calcium silicate, microcrystalline cellulose, methacrylate, shellac, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. . Aqueous media include the active ingredient or components, one or more surfactants sufficient to dissolve or suspend the active ingredient consistently through a large amount of the medium and other manufacturing additives known in the art. The other preparation additives include granulation-binding agents such as gelatin; Natural gums such as acacia, tragacanth; Starch, sodium alginate, sugar, polyvinylpyrrolidone; Cellulose derivatives such as hydroxypropylmethyl cellulose and polyvinyloxoazolidone; Pharmaceutical fillers such as lactose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, calcium sulfate, dextrose, mannitol, sucrose; If necessary, tableting lubricants such as calcium and magnesium stearate, stearic acid, talc, sterotex (alkaline stearate). “Aqueous medium” for one component of one embodiment of the invention is used within the practice of the art. Primarily refers to a water medium to which a solvent is added which, if necessary, can be mixed with water such as isopropanol or ethanol to support the active ingredient.

In the following Examples the present invention will be described in more detail. The examples are intended to illustrate the invention and are not intended to limit it.

Example  1: 1-ethyl- (E, E) -2,6-bis [2- [4- ( Pyrrolidinyl ) Phenyl ] Ethenyl ] Pyridinium  Synthesis of Chloride (6)

Step a: 2,6- Lutidine  (1) and Iodoethane  Reaction of (2) 2,6- Lutidine  Ethiopian All Generate Droid (3).

A total of 69.7 g (0.65 mole) of 2,6-lutidine (1) was mixed with 202.8 g of ethyl iodide (2) and the mixture was heated at 100 ° C overnight. The reaction mixture was cooled and 2,6-lutidine ethiodide (3) precipitated was recovered by filtration. The filtrate was reheated to 100 ° C. overnight, then cooled and filtered to give solid 2,6-lutidine ethiodide (3) of the second obtained. The two obtained are mixed, dissolved in hot anhydrous ethanol and recrystallized. The resulting solid was dissolved in hot ethanol and secondly recrystallized. The purified 2,6-lutidine ethiodide (3) was air dried to constant weight to give 107.5 g of the desired product. ¹ H-NMR was consistent with the desired material and an incorrect melting point was measured at 205-206 ° C.

Step b: 2,6- Lutidine Ethiodide  3,2,6- Lutidine Etochloride  Switch to (4).

107.5 g of 2,6-lutidine ethiodide was dissolved in 2.0 L of methanol and the solution was cooled in an ice-water bath. A total of 220 g of anhydrous hydrogen chloride gas was slowly added to the solution through a gas bubbler. During the hydrogen chloride addition the reaction temperature was kept below 30 ° C. using an ice-water bath. After all the hydrogen chloride was added, the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated to near dryness and then redissolved in 1.0 L of methanol. A total of 103 g of anhydrous hydrogen chloride gas was then injected into the mixture as a gas. After stirring for 10 minutes, the reaction mixture was concentrated in vacuo to dryness to yield 94.3 g of the desired 2,6-lutidine ethochloride (4).

Step c: 2,6- Lutidine Etochloride  (4) and 4- Pyrrolidinobenzaldehyde  (5) was reacted to give 1-ethyl- (E, E) -2,6-bis [2-4- ( Pyrrolidinyl ) Phenyl ] Ethenyl ] Pyridinium  Preparation of Chloride (6).

A mixture of 30.6 g (0.22 mole) 2,6-lutidine ethoxide (4), 75 g (0.54 mole) 4-pyrrolidinobenzaldehyde (5), 12 mL piperidine and about 2 L methanol Heated to reflux overnight. ¹ H NMR showed no reaction. No reaction occurred after the reaction mixture was heated to reflux for an additional 96 hours. An additional 12 mL of piperidine was added and heating at reflux continued. After a total of 120 hours of reflux heating, some solids started to precipitate but ¹ H NMR indicated that the desired reaction was not yet terminated. An additional 12 mL of piperidine catalyst was added and the reaction mixture was heated to reflux for an additional 24 hours. At this time, the ¹ H NMR spectrum indicated that the desired reaction was performed and terminated. The reaction mixture was slowly cooled to room temperature and filtered to give 1-ethyl- (E, E) -2,6-bis [2- [4- (pyrrolidinyl) phenyl] ethenyl] pyridinium chloride (6). The precipitated solid containing was recovered. The solid was triturated and washed three times with 100 mL of ethyl ether to remove impurities and residual methanol solvent. The solid was air dried to constant weight and vacuum dried to give 32.6 g of red crystalline 1-ethyl- (E, E) -2,6-bis [2- [4- (pyrrolidinyl) phenyl] ethenyl] Pyridinium chloride (6) was obtained-high performance liquid chromatography area percent (HPLC area%) = 98.1%, ¹ H NMR (DMSO, d ₆ ); ppm 8.16-8.14 (t, 1 H); 8.08-8.07 (d, 2 H); 7.71-7.68 (d, 1 H); 7.69-7.67 (d, 2H, J = 8.8 Hz); 7.23-7.20 (d, 1 H); 6.61-6.59 (d, 2H, J = 8.8 Hz); 4.75-4.74 (m, 2 H); 3.31 (m, 2 H); 1.98-1.96 (m, 2 H); 1.48-1.45 (t, 3 H). The reaction filtrate was concentrated to approximately half the original volume, 10 mL of piperidine was added and the dark reaction filtrate was heated to reflux for 24 hours. ¹ H NMR spectral analysis is more likely to yield more 1-ethyl- (E, E) -2,6-bis [2- [4- (pyrrolidinyl) phenyl] ethenyl] pyridinium chloride (6 by olefin isomer equilibrium. ) Was generated. Heat was removed and the reaction mixture was stirred for 48 hours at room temperature, during which a precipitate formed. The solid was recovered by filtration, triturated and washed three times with 100 mL of ethyl ether to remove impurities and residual methanol solvent. 19.2 g of additional 1-ethyl- (E, E) -2,6-bis [2- [4- (pyrrolidinyl) phenyl] ethenyl] was dried by air drying and vacuum drying the red crystalline solid to a certain weight. Pyridinium chloride (6) was obtained-HPLC area% = 97.4%, ¹ H-NMR was consistent with the product (6) of the first obtained.

Example  2: 1-ethyl- (E, E) -2,6-bis [2- [4- (dimethylamino) Phenyl ] Ethenyl ] Pyridinium  Synthesis of Chloride

A mixture of 9.0 g (0.07 mole) 2,6-rutidine etochloride, 23.6 g (0.16 mole) 4-dimethylaminobenzaldehyde, 14 mL piperidine and 350 mL methanol was heated to reflux for 77 hours. After 77 hours of reflux, high performance liquid chromatography-mass spectral analysis (LC / MS analysis) showed that the desired product was present in the reaction mixture. The reaction mixture was cooled slowly to induce precipitation and the precipitated solid was recovered by filtration. The solid was triturated and washed three times with 100 mL of ethyl ether to remove impurities and residual methanol solvent. The solid was air dried to a certain weight and vacuum dried to give 2.8 g of red crystalline 1-ethyl- (E, E) -2,6-bis [2- [4- (dimethylamino) phenyl] ethenyl] pyridine. Dinium chloride was obtained-high performance liquid chromatography area percent (HPLC area%) = 99.5%, ¹ H NMR (DMSO, d ₆ ) is consistent with the desired product. The reaction filtrate was concentrated to approximately half of the original volume. A total of 10 mL of piperidine catalyst was added and the dark solution was heated to reflux for an additional 24 hours. At that point, high performance liquid chromatography area percent analysis (HPLC A% analysis) showed that more product was produced and the 2,6-lutidine etochloride starting material was nearly extinguished. The heat was removed and the reaction concentrated in vacuo to give a heavy slurry. The precipitated solid was recovered by filtration, washed three times with 100 mL of ethyl ether and the resulting solid was air dried overnight and vacuum dried to give 13.6 g of red crystalline 1-ethyl- (E, E) -2 , 6-bis [2- [4- (dimethylamino) phenyl] ethenyl] pyridinium chloride was obtained-HPLC area% = 99%, ¹ H NMR (DMSO, d ₆ ) is consistent with the desired product.

Example  3: Synthesis of 1-ethyl- (E, E) -2,6-bis [2- [4- (diethylamino) phenyl] ethenyl] pyridinium chloride

A mixture of 9.0 g (0.07 mole) 2,6-rutidine etochloride, 28.1 g (0.16 mole) 4-diethylaminobenzaldehyde, 14 mL piperidine and 350 mL methanol was heated to reflux for 96 hours, at which time LC / MS analysis showed the desired product was present. The reaction mixture was cooled and concentrated in vacuo to afford a slurry. The solid was recovered by filtration, triturated and washed three times with 50 mL of ethyl ether. The resulting purified solid was air dried and vacuum dried to give 17.3 g of red crystalline 1-ethyl- (E, E) -2,6-bis [2- [4- (diethylamino) phenyl] ethenyl] pyridinium Chloride was obtained-high performance liquid chromatography area percent (HPLC area%) = 95%, ¹ H NMR (DMSO, d ₆ ) was consistent with the desired material and traces of starting 4-diethylaminobenzaldehyde were present.

Example  4: 1-ethyl- (E, E) -2,6-bis [2- [4- ( Pyrrolidinyl ) Phenyl ] Ethenyl ] Pyridinium  Synthesis of 4-aminobenzoate salt

52.8 g (0.12 mole) of 1-ethyl- (E, E) -2,6-bis [2- [4- (pyrrolidinyl) phenyl] ethenyl] pyridinium chloride and 18.6 g (0.12 mole) in total The sodium salt of 4-aminobenzoic acid (sodium salt of p-aminobenzoic acid, Na ⁺ PABA ⁻ ) was dissolved in 1.3 L of methanol and the mixture was stirred at room temperature for 4 days during which a precipitate formed. The reaction mixture was then filtered and the solid salts were air dried and vacuum dried to afford 28.0 g of 1-ethyl- (E, E) -2,6-bis [2- [4- (pyrrolidinyl) ) Phenyl] ethenyl] pyridinium 4-aminobenzoate salt (also called PABA salt) was obtained. The filtrate was concentrated in vacuo to give more precipitate. Separation of the second yield was carried out by filtration of the solid followed by air drying and vacuum drying, whereby 42.6 g of 1-ethyl- (E, E) -2,6-bis [2- [4 were obtained from the second yield. -(Pyrrolidinyl) phenyl] ethenyl] pyridinium 4-aminobenzoate salt (also known as PABA salt) was obtained-high performance liquid chromatography area percent (HPLC A%) first yield = 99.6% except PABA ; HPLC A% second yield = 99.9% except PABA; ¹ H NMR and mass spectral analysis of the two yields yielded the desired substance 1-ethyl- (E, E) -2,6-bis [2- [4- (pyrrolidinyl) phenyl] ethenyl] pyridinium 4 -Consistent with the structure of the aminobenzoate salt. The product may also contain 1-ethyl- (E, E) -2,6-bis [2- [4- (pyrrolidinyl) phenyl] ethenyl] pyridinium p-aminobenzoate salt or 1-ethyl- (E , E) -2,6-bis [2- [4- (pyrrolidinyl) phenyl] ethenyl] pyridinium PABA salt.

According to the method disclosed in Examples 1-3, a polar protic solvent such as methanol, ethanol, 2-propanol or the like or acetonitrile (ACN), dimethyl acetamide (DMA), dimethyl formamide (DMF), dimethyl sulfoxide Substituted and unsubstituted aromatic aldehydes or substituted and unsubstituted heteroaromatic aldehydes in a polar aprotic solvent, such as (DMSO), etc. By reacting with a dean 1,1,1-trifluoroetochloride salt and the like and a secondary amine catalyst such as piperidine and pyrrolidine to obtain all possible mixtures of the compounds indicated in the specification and claims. Applicant provides a number of compounds shown in FIGS. 1-4 illustrating some of the possible combinations of the present invention.

In the following examples, the "active ingredient" may be any of the abovementioned compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof.

Example  5: antimicrobial activity

The solution of formula I, stilbart chloride, (1% dimethylsulfoxide) was diluted with sterile water using successive half-step dilutions. 40 μl of each dilution was then pipetted onto inoculated Mueller-Hinton agar plates. The agar plates were then incubated at 35 ° C. for 24 hours and then the zone of inhibition was recorded. The minimum inhibitory concentration (MIC) was the lowest concentration of test substance that produced an inhibitory zone for the organism. The MIC of formula I for a series of organisms is shown in the table below.

Table 1: Antimicrobial Activity of Formula I

Strain MIC Streptococcus pyogenes 1.0 Streptococcus faecalis 1.0 Streptococcus algalactia 1.0 Staphylococcus aureus 0.3 Bordella Bordella bronchiseptica ) 1.0 Vibrio cholera cholerae ) 10.0 Paseuturel la is far Toshima (Pasturella multocida ) 3.0 this. E. coli > 100 Pseudomonas aerugenosa ) > 100

* The data show the minimum inhibitory concentration of formula I in μg / mL for inhibition of bacterial culture in vitro.

Example  6: antifungal activity

Fungal strains (obtained from ATCC) were grown for 18 hours at 35 ° C. in Mueller-Hinton culture. The plates were then inoculated with the culture and air dried at room temperature (22 ° C.) for about 10-15 minutes. 40 μl of Formula I (in 1% dimethylsulfoxide) and subsequent half-step dilutions were pipetted into the inoculated Mueller-Hinton agar plates. The plates were then incubated at 35 ° C. for 24 hours and then the zone of inhibition was recorded. The minimum inhibitory concentration (MIC) was the lowest concentration of test substance that produced an inhibitory zone for the organism. The antifungal activity of formula I for various fungal strains is listed in the table below.

Table 2: In vitro Inhibition of Yeast and Fungal Growth by Formula I

Creature MIC Candida albicans (Candida albicans ) <0.006 Candida Tropical faecalis (Candida tropicalis ) <0.4 Cryptococcus neoformus neoformans ) <0.4 Saccharomyces cervisciae ) <0.4 Aspergillus Fu Micah Charters (Aspergillus fumigatus ) <0.006 Aspergillus Flavor flavus ) 6.25 Fusarium solani (Fusarium solani ) <0.4 Rhizopus arrihizus ) 6.25 Microsporidium Canis canis ) 1.6 Microsporidium gypseum ) 1.6 Trichophyton equinium ) 1.6 Trichophyton Trichophyton mentagrophyt ) 1.6 Trichophyton rubrum ) 1.6 Epidermophyton floccsum ) 1.6

* The data show the minimum inhibitory concentration of formula I in μg / mL for inhibition of bacterial culture in vitro.

Example  7

Stilbad iodide was tested against a panel of plant related filamentous fungal strains. Stock solutions of compounds were prepared in DMSO at a concentration of 10,000 ppm. Additional dilutions were made using water. Tests were performed at concentrations of 125, 31, 8, 21, 0.5 and 0.125 ppm. A spore suspension of fungi was prepared. The test was performed on microtiter plates and for each fungus and each concentration, three wells were prepared. Incubation of inoculated plates was performed at 18 ° C. for 7 days. Thereafter, the optical concentration of the mycelium generated in each well was measured at 405 nm.

From the data shown in Table 3, IC 90 values (concentrations in which at least 90% fungal growth is reduced compared to control) can be assessed.

TABLE 3

Creature Related plants IC90 Alternaria solani ) potato > 125 Botrytis cinerea ) vegetable 0.5 Cochliobolus mijabeanus ) corn > 125 Colletotrichum ( colletotrichum) lagenarium ) melon 31 Fusarium Fusarium culmorum ) wheatear > 125 Phytophthora infestans ) tomato 2 Pyrenophora teres ) barley 31 Pyricularia oryzae ) rice 8 Rhizoctonia solani ) Rice vinegar 2 Septonia Tritice tritici ) Wheat leaves 2

Example  8

The data shown in Table 4 below shows various bacteria and fungi that can be treated by the stilbachel compound. The data show the overall effect of the various stilbaches compounds.

Table 4

Bell detach # MIC 80% MIC 100% MFC Alternaria species 128.89 6.25 12.5 > 100 Aspergillus flavus 112.96 3.12 6.25 6.25 Aspergillus flavus 194.99 3.12 3.12 12.5 Aspergillus flavus 107.96 6.25 12.5 25 Aspergillus flavus 141.88 12.5 25 25 Aspergillus flavus 178.03 12.5 25 > 25 Aspergillus flavus 173.03 25 25 > 25 Aspergillus fumigatus 168.95 3.12 6.25 > 25 QC A. fumigatus 168.95 3.12 6.25 > 100 QC A. fumigatus 168.95 3.12 6.25 > 100 Aspergillus fumigatus 111.02 3.12 6.25 12.5 Aspergillus fumigatus 153.90 12.5 25 25 Aspergillus fumigatus 182.99 12.5 25 > 25 Aspergillus sydowii 165.02 0.78 1.56 3.12 Aspergillus versicolor 120.02 1.56 3.12 6.25 Bipolaris spicifera 155.89 3.12 3.12 > 100 Candida albicans A39 0.39 0.39 0.39 Candida albicans 117.00 0.39 0.39 0.39 QC C. albicans 117.00 1.56 1.56 3.12 QC C. albicans 117.00 3.12 3.12 6.25 Candida albicans 117.00 0.78 1.56 3.12 Candida albicans 116.98 0.39 0.39 1.56 Candida albicans 126.97 0.39 0.78 0.78 Candida albicans 149.97 0.39 0.39 0.78 Candida albicans 159.95 0.39 0.39 1.56 Candida albicans 156.97 1.56 1.56 1.56

Table 4 (continued)

Bell detach # MIC 80% MIC 100% MFC Candida albicans (Candida albicans ) 203.03 1.56 1.56 3.12 Candida albicans (Candida albicans ) 204.03 1.56 1.56 1.56 Candida albicans (Candida albicans ) 205.03 1.56 1.56 6.25 Candida albicans (Candida albicans ) 206.03 3.12 3.12 12.5 Candida albicans (Candida albicans ) 202.03 3.12 3.12 3.12 Candida parapsissis parapsilosis ) 110.01 0.78 0.78 3.12 Candida parapsissis parapsilosis ) ATCC 22019 0.78 0.78 3.12 Candida parapsissis parapsilosis ) 109.96 1.56 1.56 3.12 Candida parapsissis parapsilosis ) 118.02 1.56 1.56 6.25 Candida parapsissis parapsilosis ) 123.00 1.56 1.56 6.25 Chaetomium species T217 1.56 3.12 > 100 Cryptococcus neoforms neoformans ) H99 0.012 0.024 1.56 Curvularia lunata ) 141.90 1.56 3.12 > 100 Curvularia lunata ) 110.90 3.12 3.12 > 100 Cabularia Lunata v. Curvularia lunata v. aeria ) 104.89 3.12 6.25 > 100 Curvularia lunata ) 146.90 6.25 6.25 > 100 Penicillium Aurantithiogriseum aurantiogriseum ) 135.02 6.25 12.5 > 100 Penicillium chrysogenum ) 119.02 0.78 0.78 12.5

Table 4 (continued)

Bell detach # MIC 80% MIC 100% MFC Rhizopus duck oryzae ) 172.86 1.56 6.25 > 100 Rhizopus duck oryzae ) 18288 3.12 6.25 > 100 Rhizopus duck oryzae ) 318.86 3.12 6.25 > 100 Rhizopus duck oryzae ) 117.89 6.25 6.25 12.5 Rhizopus duck oryzae ) 127.88 12.5 12.5 > 25 Rhizopus duck oryzae ) 181.88 12.5 12.5 > 25 Rhodotorula mucilaginosa ) 213.03 1.56 3.12 6.25 Rhodotorula mucilaginosa ) 207.03 3.12 3.12 3.12 Rhodotorula mucilaginosa ) 209.03 3.12 6.25 6.25 Rhodotorula mucilaginosa ) 210.03 3.12 3.12 3.12 Rhodotorula mucilaginosa ) 211.03 6.25 6.25 6.25

Example  9

(1) tablet formulation

(i) oral

mg / tablet

A B C Active ingredient 25 25 25 Avicel ^TM 13 0 7 Starch (corn) 0 9 0 Starch (preliminary, NF15) 0 0 32 Starch Glycolate Sodium Salt 5 0 0 Povidone ^TM 3 3 0 Magnesium stearate One One One

(ii) sublingual

mg / tablet

D E Active ingredient 25 25 Avicel ^TM 0 10 Lactose 0 36 Mannitol 51 75 Sucrose 0 3 acacia 0 3 Povidone ^TM 3 0 Magnesium stearate One One

Formulations A through E can be prepared by first wet granulating the six components with Providone ^™ , adding magnesium stearate, and pressing.

(iii) Buccal

mg / tablet

Active ingredient 25 Hydroxypropylmethylcellulose (HMPC) 25 Polycarbophil ^TM 39 Magnesium stearate One

The formulations may be prepared by direct compression of the mixed components.

(2) capsule formulation

(i) powder

mg / capsules

F G Active ingredient 25 25 Avicel ^TM 45 0 Lactose 153 0 Starch (1500 NF) 0 117 Starch Glycolate Sodium Salt 0 6 Magnesium stearate 2 2

Formulations F and G can be prepared by mixing the components and filling two portions of hard gelatin capsules with the resulting mixture.

(ii) liquid filling

mg / capsules

H I Active ingredient 25 25 Macrogol ^TM 4000 BP 200 0 lecithin 0 100 Arachis oil 0 100

Formulation H can be prepared by dissolving Macrogol ^™ 4000 BP, dispersing the active ingredient in the lysate and filling it with two portions of hard gelatin capsules. Formulation I can be prepared by dispersing the active ingredient in lecithin and arachis oil and filling soft, resilient capsules with the dispersion.

(iii) controlled release

mg / tablet

Active ingredient 25 Avicel 123 Lactose 62 Triethyl citrate 3 Ethyl cellulose 12

The formulation can be prepared by extruding the preceding four components and spheronizing and drying the extrudate. The dried pellets are coated with ethyl cellulose, a release control membrane, and filled into two portions of hard gelatin capsules.

Inhalation Powder Capsule

Active Ingredient (0.5-7.0 μm Powder) 1.0 mg Lactose (30-90 μm Powder) 49.0 mg

The powder was mixed until homogeneous and filled into hard gelatine capsules of appropriate size (50 mg per capsule).

Inhalation aerosol

Active Ingredient (0.5-7.0 μm Powder) 50 mg Sorbitan Trioleate 100 mg Saccharin Sodium (0.5-7.0 μm Powder) 5 mg menthol 2 mg Trifluoromethane 4.2 g Dichlorodifluoromethane Suitable amount up to 10 mL

Sorbitan trioleate and methanol are dissolved in trichlorofluoromethane. Saccharin sodium and the active ingredient were dispersed in the mixture and transferred to a suitable aerosol bottle and injected with dichlorofluoromethane through a valve system. The composition provides 0.5 mg of active ingredient in each 100 μl dose.

Topical solution

ingredient amount Equation I 200 mg Ethyl alcohol, USP (95% v / v) 100 mL

The compound of formula I was dissolved directly in alcohol and placed in a amber glass vial. Skin application of the resulting 0.2% solution can be achieved through application with a cotton swab or through a permeable, absorbent cap applied to the infected sheath.

Example  10

Biological activity

Water-soluble creams for external (skin), vaginal and rectal applications

Compound of formula I

ingredient amount Equation I 500 mg Butanediol 100 mL

The compound of formula I was suspended by mixing in butane and the resulting cream applied topically.

Carrageenan pleurisy assay

Anti-inflammatory activity of the compounds of the present invention was determined using Vinegar, R, et al., Proc. Soc. Exp. Biol. Med., 1981, 168, 24-32 was determined by the procedure. The carrageenan dose was 0.075 mg / rat. 4 hours after carrageenan injection, the lead exudate was recovered. Acute anti-inflammatory activity was determined by pleural edema from the negative (vehicle) control and inhibition of inflammatory cells (neutrophils).

2) Acetic Colitis Assay

Anti-inflammatory activity of the compounds of the present invention was determined in acetic colitis rat model using the procedure of Fretland, D., et al., 1990, 255: 572-576 in 275 + 25 g male Lewis rats. Compounds were administered 24, 16 and 4 hours prior to injection of 40 seconds of 3% acetic acid solution at 6 cm near the colon orally or rectally under shallow anesthesia. The colon was immediately washed with 5 cc saline. After 24 hours the rats were sacrificed and the 6 cm close colon was removed. Neutrophil inflammation was determined by measuring MPO levels in colonic mucosa removed from the rats. Anti-inflammatory activity was determined by edema formation and inhibition of mucosal MPO levels compared to negative control (vehicle).

3) antimicrobial activity

The solution of formula I (1% dimethylsulfoxide) was diluted using sequential water with continuous half-step dilution. 40 μl of each dilution was then pipetted onto inoculated Mueller-Hinton agar plates. The agar plates were then incubated at 35 ° C. for 24 hours and then the zone of inhibition was recorded. The minimum inhibitory concentration (MIC) was the lowest concentration of test substance that produced an inhibitory zone for the organism. The MIC of formula I for a series of organisms is described in Table 2 above.

4) antifungal activity

Fungal strains (obtained from ATCC) were grown for 18 hours at 35 ° C. in Mueller-Hinton culture. The plates were then inoculated with the culture and air dried at room temperature (22 ° C.) for about 10-15 minutes. 40 μl of Formula I (in 1% dimethylsulfoxide) and subsequent half-step dilutions were pipetted into the inoculated Mueller-Hinton agar plates. The plates were then incubated at 35 ° C. for 24 hours and then the zone of inhibition was recorded. The minimum inhibitory concentration (MIC) was the lowest concentration of test substance that produced an inhibitory zone for the organism. Table 6 below shows the antifungal activity of Formula I against various fungal strains.

Table 5: Comparison of Formula I and Other Anti-inflammatory Drugs in Carrageenan Pleurisy Assays in Male Lewis Rats

compound Dose (μg / rat; intrapleural) % Suppression WBC % Suppression Exudate Equation I 0.2 32 25 Equation I 1.0 41 40 Equation I 5.0 76 60 Dexamethasone 2.0 8 10 Dexamethasone 10.0 29 41 Dexamethasone 50.0 68 83 Prednisolone 50 23 25 Prednisolone 250 32 30 Prednisolone 1250 97 55

The results were expressed as% inhibition of exudate volume resulting from infiltration of white blood cells (wbc) and intrapleural infiltration of carrageenan. Drug is administered 1 hour after carrageenan; The measurement was performed after 4 hours.

Table 6: Comparison of Formula I and Other Anti-inflammatory Drugs in Acetic Acid Colitis Assay in Male Lewis Rats

compound Dose (mg / kg (po)) % Inhibitory tissue swelling (edema) % Suppression MPO (u / cm) Equation I 5 36 39 Equation I 20 47 37 Sulfasalin 100 10 20 Sulfasalin 300 14 16 Prednisolone 3 44 41 Prednisolone 12 40 46

Table 7: Comparison of Formula I and Other Anti-inflammatory Drugs in the Treatment of Vaginal Candidiasis in Female Charles River Mice

compound Cured Improving Diluent (butanediol) 4/10 0/10 Equation I 9/10 1/10 Chlortrimazole 7/10 2/10

Mice infected with candida albicans in the vagina were started 6 hours after infection and treated with 0.025 mL of the treatment daily for 4 days. The concentration of formula I was 0.5% (w / v) and the concentration of chlortrimazole was 1% (w / v).

Table 8: In vitro Inhibition of Yeast and Fungal Growth by Formula I

Creature MIC Candida albicans (Candida albicans ) <0.006 Candida Tropical faecalis (Candida tropicalis ) <0.4 Cryptococcus neoformus neoformans ) <0.4 Saccharomyces cervisciae ) <0.4 Aspergillus Fu Micah Charters (Aspergillus fumigatus ) <0.006 Aspergillus Flavor flavus ) 6.25 Fusarium solani (Fusarium solani ) <0.4 Rhizopus arrihizus ) 6.25 Microsporidium Canis canis ) 1.6 Microsporidium gypseum ) 1.6 Trichophyton equinium ) 1.6 Trichophyton Trichophyton mentagrophyt ) 1.6 Trichophyton rubrum ) 1.6 Epidermophyton floccsum ) 1.6

* The data show the minimum inhibitory concentration of formula I in μg / mL for inhibition of bacterial culture in vitro.

Table 9: In vivo Pharmacological and Toxicological Effects of Stilva Salt

Assay , Species, route of administration, infusion volume Active dose (concentration) Signs of toxicity comment Candida vaginitis, mouse, topical, 25 μl 100 μM None, normal histology No infection at 100 μM Allergic pleurisy, rat, topical, 250 μl 12 μM none Inhibition of Exudate Formation & LTs Candida vaginitis, mouse, topical, 25 μl 100 μM None, normal histology No infection at 100 μM Allergic pleurisy, rat, topical, 250 μl 12μM82μM None Formation of Exudates & Inhibition of LTs Delay Response (Neutral Ball) Allergic synovitis, rat, topical, 5 μl 230 μM none Reduced # of neutrophils in the joints Anti-inflammatory activity, rat leg, topical application, 100 μl 0.5% none Suppression of neutrophil-mediated edema formation Insect Repellent Activity, Human, Oral, Capsule 1-10 mg / kg Weak stomach irritation No systemic side effects Mast cell release, rat, intradermal, 100 μl 2mM Weak edema Leukotriene Synthesis, Rat Pleural Cells, Topical, 25 μl 0.008mg / kg none ED ₅₀ dose Eye irritation, rabbit, topical, 30 μl 2mM Non-irritating

Table 10: Efficacy of stilbat salt +/- prednisolone in rodent inflammation model

4-hour carrageenan pleurisy

compound Dose mg / kg % Suppress edema % Suppression Neutrophils Prednisolone 0.02 31 21 Stiletto Salt 0.0004 38 18 Prednisolone + Stilvajan Salt 0.02 + 0.0004 67 56 result additive additive

4-hour allergic pleurisy

compound Dose mg / kg % Suppress edema % Suppression Neutrophils Prednisolone 0.004 33 25 Stiletto Salt 0.002 19 10 Prednisolone + Stilvajan Salt 0.004 + 0.002 57 40 result additive additive

4-hour allergic synovitis

compound Dose mg / kg % Suppress edema % Suppression Neutrophils Prednisolone 0.05 36 37 Stiletto Salt 0.002 24 28 Prednisolone + Stilvajan Salt 0.05 + 0.02 67 72 result additive additive

Example  11

In vitro screening

Stock solutions of each compound were prepared in DMSO at a concentration of 10,000 ppm. Additional dilutions were made using water. Tests were performed at concentrations of 125, 31, 8, 21, 0.5 and 0.125 ppm. Spore suspensions of the following fungi were prepared: Alternaria solani , Botrytis cinerea ), Cochiobolus mijabeanus , Colletotrichum lagenarium , Fusarium culmorum ), Phytophthora infestans , Pyrenophora teres ), Pyricularia oryzae , Rhizoctonia solani ) and ceftria triciti tritici ).

The test was performed on microtiter plates and for each fungus and each concentration, three wells were prepared. Incubation of inoculated plates was performed at 18 ° C. for 7 days. Thereafter, the optical concentration of the mycelium generated in each well was measured at 405 nm. From the data generated, the IC 90 values (concentrations that reduce at least 90% fungal growth compared to control) can be assessed.

In vivo vivo )-Separation Leaf Assay

In this model, isolated leaves of appropriate host plants were placed on water agar. The leaves were treated with 20 μl cm 2 of 15 ppm solution of each compound prepared from 10,000 ppm stock solution in DMSO. The treated leaves were dried for 24 hours, and then inoculated with the following fungal species (host plants in parentheses); The exception for wheat brown rust ( Puccinia triticina ) was inoculated with leaves 24 hours prior to application of the test compound: Blumeria graminis f.sp. Tritsi ( Blumeria) graminis , f. sp . tritici ) (wheat), Fusarium culmorum (barley), Phaeosphaeria nodorurm ) (wheat), Phytophthora infestans (tomato), Puccinia triticina (wheat) and Pyricularia oyrzae ) (rice).

The leaves were then incubated at 18 ° C. with a 12 hour light cycle. The incubation period was up to 7 days. Three were performed for each.

In vivo vivo ) -Greenhouse Screening

The compounds were sprayed at 250, 63 and 16 ppm to the test plants, inoculation of the treated plants was carried out 24 hours after the treatment, with the exception of leaves inoculated 24 hours before the treatment in the case of wheat brown rust. The following combinations of pathogens / host plants were included in the trial: Alternaria solani ) / tomatoes, Botrytis cinerea / bell peppers, Phytophthora infestans ) / tomato and fuchsia tritini triticina ) / wheat.

Cultivation was performed under climatic conditions favorable to the growth of fungal pathogens. Disease onset was assessed 7 days after inoculation.

Overall results

Most test compounds showed extensive in vitro activity, and in some cases were achieved at very low concentrations.

Under greenhouse conditions and with intact plants, a limited degree of activity could be identified at high concentrations (250 ppm). Activity was shown in Alternaria solani and Phytophthora infestans .

Example  12

Stilbad iodide was tested against a panel of plant related filamentous fungal strains. Stock solutions of compounds were prepared in DMSO at a concentration of 10,000 ppm. Additional dilutions were made using water. Tests were performed at concentrations of 125, 31, 8, 21, 0.5 and 0.125 ppm. A spore suspension of fungi was prepared. The test was performed on microtiter plates and for each fungus and each concentration, three wells were prepared. Incubation of inoculated plates was performed at 18 ° C. for 7 days. Thereafter, the optical concentration of the mycelium generated in each well was measured at 405 nm.

From the data shown in Table 11, IC 90 values (concentrations in which at least 90% fungal growth is reduced compared to control) can be assessed.

Table 11

Creature Related plants IC90 Alternaria solani ) potato > 125 Botrytis cinerea ) vegetable 0.5 Cochliobolus mijabeanus ) corn > 125 Colletotrichum ( colletotrichum) lagenarium ) melon 31 Fusarium Fusarium culmorum ) wheatear > 125 Phytophthora infestans ) tomato 2 Pyrenophora teres ) barley 31 Pyricularia oryzae ) rice 8 Rhizoctonia solani ) Rice vinegar 2 Septonia Tritice tritici ) Wheat leaves 2

In the present specification, particularly preferred embodiments of the present invention have been described, and although specific terms are used, they are used in the sense of general description and are not intended to limit the scope of the invention as set forth in the following claims. .

Claims (47)

Compounds or solvates thereof comprising the following formula: Wherein said compound is an E, E configuration; The NR ₁ R ₂ and NR ₃ R ₄ moieties are in the ortho, meta or para position; X ⁻ is an anionic salt; _{R 1, R 2, R 3} , or R ₄ are independently selected from the group consisting of methyl, ethyl, C _{1 -10-alkyl} (linear or branched), and alkenes (linear or branched), R _1, and R ₂ or R ₃ and R ₄ together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring; R ₅ is methyl, ethyl, C _{1 -10-alkyl} (linear or branched), alkenes (linear or branched), alkynes, n- propyl, i- propyl, n- butyl, i- butyl, substituted and unsubstituted aryl Moieties and substituted and unsubstituted benzyl moieties. The method of claim 1 wherein, X ^- is fluoride, chloride, bromide, iodide halide (halide), mesylate, tosylate, naphthyl acrylate, nosil acrylate, para-aminobenzoate, lauryl sulfate, 2,4 -Dihydroxy benzophenone, 2- (2-hydroxy-5'-methylphenyl) benzotriazole, benzenesulfonate, besylate, ethyl 2-cyano-3,3-diphenyl acrylate and 5-butyl phenyl Compound selected from the group consisting of salicylates. The organic metal of claim 1 or 2, wherein R ₅ is (CH ₂ ) _n -MR ₆ , wherein n is a number from 1 to 6, and M is an organic metal selected from the group consisting of tin, silicon, and germanium And R ₆ is selected from the group consisting of substituted or unsubstituted propyl, butyl, and alkyl. The compound of claim 1, wherein the compound is 1-ethyl- (E, E) -2,6-bis [2- [4, substantially free of any other arrangement of isomers. -(Pyrrolidinyl) phenyl] ethenyl] pyridinium chloride, 1-ethyl- (E, E) -2,6-bis [2- [4- (dimethylamino) phenyl] ethenyl] pyridinium chloride, 1 -Ethyl- (E, E) -2,6-bis [2- [4- (diethylamino) phenyl] ethenyl] pyridinium chloride, 1-ethyl- (E, E) -2,6-bis [ 2- [4- (pyrrolidinyl) phenyl] ethenyl] pyridinium 4-aminobenzoate salt and 1-methyl- (E, E) -2,6-bis [2- [4- (pyrrolidinyl) Phenyl] ethenyl] pyridinium chloride. A method for treating an industrial product having fungal growth comprising administering to the site to be grown the effective amount of the compound of any one of claims 1 to 4. The method of claim 5, wherein the industrial product is wood, air ducts, plates, decks, pipes, stucco, tiles, paints paint, insulation, roofs, building materials, metals, computer parts, food packaging and substrates. A composition comprising a compound of the formula or a solvate thereof and excipients: Wherein said compound is an E, E configuration; The NR ₁ R ₂ and NR ₃ R ₄ moieties are in the ortho, meta or para position; X ⁻ is an anionic salt; _{R 1, R 2, R 3} , or R ₄ are independently selected from the group consisting of methyl, ethyl, C _{1 -10-alkyl} (linear or branched), and alkenes (linear or branched), R _1, and R ₂ or R ₃ and R ₄ together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring; R ₅ is methyl, ethyl, C _{1 -10-alkyl} (linear or branched), alkenes (linear or branched), alkynes, n- propyl, i- propyl, n- butyl, i- butyl, substituted and unsubstituted aryl Moieties and substituted and unsubstituted benzyl moieties. A method of making a composition according to claim 7 comprising administering HCl to the composition. The method of claim 7, X ^- is fluoride, chloride, bromide, iodide halide (halide), mesylate, tosylate, naphthyl acrylate, nosil acrylate, para-aminobenzoate, lauryl sulfate, 2,4 -Dihydroxy benzophenone, 2- (2-hydroxy-5'-methylphenyl) benzotriazole, ethyl 2-cyano-3,3-diphenyl acrylate, benzenesulfonate, besylate and 5-butyl phenyl Composition selected from the group consisting of salicylates. 8. The compound of claim 7, wherein the compound is 1-ethyl- (E, E) -2,6-bis [2- [4- (pyrrolidinyl) phenyl] substantially free of any other arrangement of isomers. Ethenyl] pyridinium chloride. 8. The compound of claim 7, wherein R ₅ is (CH ₂ ) _n -MR ₆ , where n is a number from 1 to 6, M is an organometallic compound selected from the group consisting of tin, silicon, and germanium, ₆ is selected from the group consisting of substituted or unsubstituted propyl, butyl, and alkyl. 8. The composition of claim 7, wherein the compound is 1-methyl- (E, E) -2,6-bis [2- [4- (pyrrolidinyl) phenyl] ethenyl] pyridinium chloride. 8. The composition of claim 7, further comprising fungicides and / or fungicides. 8. The composition of claim 7, further comprising a pesticide. 8. The composition of claim 7, wherein said composition is encapsulated in an emulsion or microcapsules. The composition of claim 15, wherein the microcapsules are time-release capsules. 8. The composition of claim 7, wherein said composition is present in sustained release or in non-sustained release. A method of controlling fungi and / or bacteria comprising administering a compound of the formula or a solvate thereof: In the above, the NR ₁ R ₂ and NR ₃ R ₄ moieties are in the ortho, meta or para position; X ⁻ is an anionic salt; _{R 1, R 2, R 3} , or R ₄ are independently selected from the group consisting of methyl, ethyl, C _{1 -10-alkyl} (linear or branched), and alkenes (linear or branched), R _1, and R ₂ or R ₃ and R ₄ together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring; R ₅ is methyl, ethyl, C _{1 -10-alkyl} (linear or branched), alkenes (linear or branched), alkynes, n- propyl, i- propyl, n- butyl, i- butyl, substituted and unsubstituted aryl Moieties and substituted and unsubstituted benzyl moieties. A method of treating inflammation in a subject comprising topically administering to a subject in need thereof a composition comprising Formula I or a solvate thereof: In the above, the NR ₁ R ₂ and NR ₃ R ₄ moieties are in the ortho, meta or para position; X ⁻ is an anionic salt; _{R 1, R 2, R 3} , or R ₄ are independently selected from the group consisting of methyl, ethyl, C _{1 -10-alkyl} (linear or branched), and alkenes (linear or branched), R _1, and R ₂ or R ₃ and R ₄ together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring; R ₅ is methyl, ethyl, C _{1 -10-alkyl} (linear or branched), alkenes (linear or branched), alkynes, n- propyl, i- propyl, n- butyl, i- butyl, substituted and unsubstituted aryl Moieties and substituted and unsubstituted benzyl moieties. A method of treating infection in a subject comprising administering to a subject in need thereof a composition comprising Formula I or a solvate thereof: In the above, the NR ₁ R ₂ and NR ₃ R ₄ moieties are in the ortho, meta or para position; X ⁻ is an anionic salt; _{R 1, R 2, R 3} , or R ₄ are independently selected from the group consisting of methyl, ethyl, C _{1 -10-alkyl} (linear or branched), and alkenes (linear or branched), R _1, and R ₂ or R ₃ and R ₄ together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring; R ₅ is methyl, ethyl, C _{1 -10-alkyl} (linear or branched), alkenes (linear or branched), alkynes, n- propyl, i- propyl, n- butyl, i- butyl, substituted and unsubstituted aryl Moieties and substituted and unsubstituted benzyl moieties. A method of treating an autoimmune disease in a subject comprising administering to a subject in need thereof a composition comprising formula I or a solvate thereof: In the above, the NR ₁ R ₂ and NR ₃ R ₄ moieties are in the ortho, meta or para position; X ⁻ is an anionic salt; _{R 1, R 2, R 3} , or R ₄ are independently selected from the group consisting of methyl, ethyl, C _{1 -10-alkyl} (linear or branched), and alkenes (linear or branched), R _1, and R ₂ or R ₃ and R ₄ together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring; R ₅ is methyl, ethyl, C _{1 -10-alkyl} (linear or branched), alkenes (linear or branched), alkynes, n- propyl, i- propyl, n- butyl, i- butyl, substituted and unsubstituted aryl Moieties and substituted and unsubstituted benzyl moieties. A method of treating a fungal or bacterial infection in a subject comprising administering to a subject in need thereof a composition comprising formula I or a solvate thereof: In the above, the NR ₁ R ₂ and NR ₃ R ₄ moieties are in the ortho, meta or para position; X ⁻ is an anionic salt; _{R 1, R 2, R 3} , or R ₄ are independently selected from the group consisting of methyl, ethyl, C _{1 -10-alkyl} (linear or branched), and alkenes (linear or branched), R _1, and R ₂ or R ₃ and R ₄ together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring; R ₅ is methyl, ethyl, C _{1 -10-alkyl} (linear or branched), alkenes (linear or branched), alkynes, n- propyl, i- propyl, n- butyl, i- butyl, substituted and unsubstituted aryl Moieties and substituted and unsubstituted benzyl moieties. A method of preventing fungal infection of a plant comprising contacting a plant during the growth stage with a compound comprising the following formula or a solvate thereof: In the above, the NR ₁ R ₂ and NR ₃ R ₄ moieties are in the ortho, meta or para position; X ⁻ is an anionic salt; R ₁ , R ₂ , R ₃ , or R ₄ are independently selected from the group consisting of methyl, ethyl, C _1-10 alkyl (linear or branched), and alkene (linear or branched), or R ₁ and R ₂ or R ₃ and R ₄ together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring; R ₅ is methyl, ethyl, C _1-10 alkyl (linear or branched), alkene (linear or branched), alkyne, n-propyl, i-propyl, n-butyl, i-butyl, substituted and unsubstituted aryl Moieties and substituted and unsubstituted benzyl moieties. 24. The method of any one of claims 18 to 23, wherein the NR moiety is in the para position, X is Cl ^- and R ₅ is methyl or ethyl. 24. The method of any one of claims 18 and 22-23, wherein said method of controlling fungi and / or bacteria further comprises binding and containing fungi and / or bacteria in the same region. How to. 24. The method of any one of claims 18 and 22-23, wherein the composition is administered before fungal growth occurs. 24. The compound of any one of claims 18 to 23, wherein R ₅ is (CH ₂ ) _n -MR ₆ , wherein n is a number from 1 to 6 and M is from the group consisting of tin, silicon, and germanium. An organometallic compound selected, wherein R ₆ is selected from the group consisting of substituted or unsubstituted propyl, butyl, and alkyl. 24. The method of any one of claims 18 and 22-23, wherein said composition is administered after fungal growth has occurred. 24. The method of any one of claims 18 and 22-23, wherein the composition is administered to an industrial substance. 30. The method of claim 29, wherein the industrial material is sheetrock, lumber, decking, flooring, roofing, carpet, wallpaper, paneling, cloth leakage protection. And is selected from the group consisting of cloth caulking, mortars, tiles, grouts, binders, adhesives, paints, coatings, sealants and stucco. 19. The method of claim 18, wherein the method comprises controlling fungi and / or bacteria by reducing fungi and / or bacteria in food packaging systems, medical products, substrates, plastics, paper and foam. . 20. The method of claim 19, wherein the inflammation is selected from the group consisting of allergic rhinitis, otitis externa, uveitis, sinusitis, asthma, adult respiratory distress syndrome, bronchitis, laryngitis, thrush and cystic fibrosis. The method of claim 21, wherein the immune disease is allergic rhinitis, otitis externa, sinusitis, asthma, adult respiratory distress syndrome, bronchitis, laryngitis, thrush, cystic fibrosis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, uveitis, conjunctivitis, Colorectal inflammation, Crohn's disease, ulcerative colitis, terminal proctitis, psoriasis, eczema, dermatitis, allergic itching, local fungal infections, gums, periodontitis, coronary artery infarction, chronic inflammation, asthma, adult respiratory distress syndrome, And rhinitis, chronic rhinosinusitis, oropharyngeal candidiasis, bronchitis, laryngitis, cystic fibrosis, and striated muscle hyperplasia. 24. The method of any one of claims 18 to 23, wherein the method further comprises administering organotin, organosilicon, or organogermanium. 24. The method of claim 23, wherein the seed of the plant is immersed in a composition comprising the strain before transplanting the seed of the plant in the plant growth medium and growing the plant. The method of claim 23, wherein the plant comprises seedlings or seeds. The fungal infection according to any one of claims 19 to 21, wherein the fungal infection consists of ringworm ringworm, head ringworm ringworm, body ringworm ringworm, stumps, nail fungal disease, scalp disease, ringworm, candidiasis, rhinosinusitis and allergic rhinitis. And bacterial infection is selected from the group consisting of acne, uveitis, rhinosinusitis and allergic rhinitis. 24. The method of any one of claims 18 to 23, wherein R ₅ is an ultraviolet sunscreen or ultraviolet absorber. The method of claim 38, wherein the sunscreen or ultraviolet absorbent And H ₃ C (H ₂ C) (H ₂ C) ₁₀ -O-SO ₃ ^- Na ⁺ . A microcapsule comprising a composition comprising a compound of formula I or a solvate, excipient and photosensitive material thereof: In the above, the NR ₁ R ₂ and NR ₃ R ₄ moieties are in the ortho, meta or para position; X ⁻ is an anionic salt; _{R 1, R 2, R 3} , or R ₄ are independently selected from the group consisting of methyl, ethyl, C _{1 -10-alkyl} (linear or branched), and alkenes (linear or branched), R _1, and R ₂ or R ₃ and R ₄ together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring; R ₅ is methyl, ethyl, C _{1 -10-alkyl} (linear or branched), alkenes (linear or branched), alkynes, n- propyl, i- propyl, n- butyl, i- butyl, substituted and unsubstituted aryl Moieties and substituted and unsubstituted benzyl moieties. 41. The microcapsule of claim 40, wherein said photosensitive material absorbs ultraviolet radiation. 41. The microcapsule of claim 40, wherein said photosensitive material blocks ultraviolet radiation. The microcapsule according to claim 40, wherein the ratio of said photosensitive material to the compound of formula I is 1:10. A method for controlling insects comprising administering a composition comprising a compound of Formula I or a solvate thereof: In the above, the NR ₁ R ₂ and NR ₃ R ₄ moieties are in the ortho, meta or para position; X ⁻ is an anionic salt; _{R 1, R 2, R 3} , or R ₄ are independently selected from the group consisting of methyl, ethyl, C _{1 -10-alkyl} (linear or branched), and alkenes (linear or branched), R _1, and R ₂ or R ₃ and R ₄ together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring; R ₅ is methyl, ethyl, C _{1 -10-alkyl} (linear or branched), alkenes (linear or branched), alkynes, n- propyl, i- propyl, n- butyl, i- butyl, and consisting of a benzyl radical Selected from the group. 45. The method of claim 44, wherein said composition is administered to wastewater. Compounds or solvates thereof comprising the following formula: In the above, n is a number from 1 to 5; Z is selected from the group consisting of C, N, O, S and halogen; The ZR ₁ R ₂ and ZR ₃ R ₄ moieties are in the ortho, meta or para position; X ⁻ is an anionic salt; _{R 1, R 2, R 3} , or R ₄ is not present (nothing), the group consisting of hydrogen, methyl, ethyl, C _{1 -10-alkyl} (linear or branched), and alkenes (linear or branched) Independently selected from R ₁ and R ₂ or R ₃ and R ₄ together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring; R ₅ is methyl, ethyl, C _{1 -10-alkyl} (linear or branched), alkenes (linear or branched), alkynes, n- propyl, i- propyl, n- butyl, i- butyl, substituted and unsubstituted aryl Moieties and substituted and unsubstituted benzyl moieties, provided that the compound is 1-ethyl- (Z, Z), (Z, E) or (E, Z) -2,6-bis Not [2- [4- (pyrrolidinyl) phenyl] ethenyl] pyridinium chloride. 47. The compound of claim 46, wherein said compound is in an E, E configuration.